WO2015179414A1 - Anthelmintic compounds - Google Patents

Anthelmintic compounds Download PDF

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Publication number
WO2015179414A1
WO2015179414A1 PCT/US2015/031599 US2015031599W WO2015179414A1 WO 2015179414 A1 WO2015179414 A1 WO 2015179414A1 US 2015031599 W US2015031599 W US 2015031599W WO 2015179414 A1 WO2015179414 A1 WO 2015179414A1
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WIPO (PCT)
Prior art keywords
alkyl
haloalkyl
halogen
hydroxy
ring
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PCT/US2015/031599
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English (en)
French (fr)
Inventor
Alan Long
Srinivas Reddy GURRALA
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Merial, Inc.
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Publication date
Priority to MX2016015090A priority Critical patent/MX361606B/es
Priority to CN201580034873.7A priority patent/CN106536518B/zh
Priority to ES15726481T priority patent/ES2842592T3/es
Priority to CA2949511A priority patent/CA2949511A1/en
Priority to US15/311,848 priority patent/US10045979B2/en
Priority to JP2016568820A priority patent/JP6616786B2/ja
Application filed by Merial, Inc. filed Critical Merial, Inc.
Priority to EP15726481.3A priority patent/EP3145925B1/en
Priority to AU2015264336A priority patent/AU2015264336B2/en
Priority to NZ726874A priority patent/NZ726874A/en
Publication of WO2015179414A1 publication Critical patent/WO2015179414A1/en
Priority to US16/054,101 priority patent/US10463661B2/en
Priority to AU2018271390A priority patent/AU2018271390B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A61K31/06—Phenols the aromatic ring being substituted by nitro groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems
    • H—ELECTRICITY
    • H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
    • H05B—ELECTRIC HEATING; ELECTRIC LIGHT SOURCES NOT OTHERWISE PROVIDED FOR; CIRCUIT ARRANGEMENTS FOR ELECTRIC LIGHT SOURCES, IN GENERAL
    • H05B41/00—Circuit arrangements or apparatus for igniting or operating discharge lamps
    • H05B41/02—Details
    • H05B41/04—Starting switches
    • H05B41/06—Starting switches thermal only

Definitions

  • variables Y and Z is a bicyclic carbocyclyl or heterocyclyl group.
  • Variables Y, Xi, X 2 , X 3 , X 4 , X5, X , X7, Xs and Z are as defined below wherein at least one of X2 or X7 is a linker LI 9, L20 or L21 as defined herein.
  • the invention also relates to parasiticidal compositions comprising the compounds, and methods and uses of the compounds for treating and preventing parasitic infections and infestations in animals.
  • ectoparasites such as insects
  • endoparasites such as nematodes and other worms.
  • domesticated animals such as cats and dogs, are often infested with one or more of the following ectoparasites:
  • - fleas e.g. Ctenocephalides spp., such as Ctenocephalides felis and the like
  • - ticks e.g. Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyoma spp., and the like
  • Ctenocephalides spp. such as Ctenocephalides felis and the like
  • ticks e.g. Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyoma spp., and the like
  • - lice e.g. Trichodectes spp., Cheyletiella spp., Linognathus spp. and the like
  • Trichodectes spp. Cheyletiella spp., Linognathus spp. and the like
  • Fleas are a particular problem because not only do they adversely affect the health of the animal or human, but they also cause a great deal of psychological stress. Moreover, fleas may also transmit pathogenic agents to animals and humans, such as tapeworm (Dipylidium caninum).
  • ticks are also harmful to the physical and psychological health of the animal or human.
  • Major diseases which may be transmitted by ticks include borrelioses (Lyme disease caused by Borrelia burgdorferi), babesioses (or piroplasmoses caused by Babesia spp.) and rickettsioses (e.g. Rocky Mountain spotted fever).
  • Ticks also release toxins which cause inflammation or paralysis in the host. Occasionally, these toxins are fatal to the host.
  • farm animals are also susceptible to parasite infestations.
  • cattle are affected by a large number of parasites.
  • Parasites prevalent among cattle in some regions are ticks of the genus Rhipicephalus, especially those of the species microplus (cattle tick), decoloratus and annulatus.
  • Ticks such as Rhipicephalus microplus (formerly Boophilus microplus) are difficult to control because they lay eggs in the pasture where farm animals graze.
  • This species of ticks is considered a one-host tick and spends immature and adult stages on one animal before the female engorges and falls off the host to lay eggs in the environment. The life cycle of the tick is approximately three to four weeks.
  • helminthiasis which is caused by of parasitic worms categorized as cestodes (tapeworm), nematodes (roundworm) and trematodes (flatworm or flukes).
  • cestodes tapeworm
  • nematodes roundworm
  • trematodes flatworm or flukes
  • parasites which occur in the gastrointestinal tract of animals and humans include Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichiris, Enterobius and parasites which are found in the blood or other tissues and organs such as filarial worms and the extra intestinal stages of Strogyloides , Toxocara and Trichinella.
  • the present invention is directed to novel and inventive anthelmintic compounds of formulae (I), (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC) and (IC-1):
  • compositions comprising the compounds in combination with a pharmaceutically acceptable carrier or diluent, with the proviso that at least one of X2 or X7 and at least one of Ring A or Ring B is a linker LI 9, L20 or L21 as defined herein or a spirocyclic carbocyclic ring linker, a heterocyclic ring linker comprising two heterocyclic rings or a carbocyclic -heterocyclic ring system joined at one carbon, wherein each ring of the spirocyclic linker contains 4, 5 or 6 ring atoms.
  • the compounds of the invention are intended to encompass racemic mixtures, specific stereoisomers and tautomeric forms of the compound.
  • Another aspect of the invention is a salt form of the compound of the invention.
  • solid state forms of the compounds of the invention which consists of crystalline forms including single crystals, nanocrystals, co- crystals, molecular complexes, hydrates, anhydrates, solvates, desolvates, clathrates and inclusion complexes and non-crystalline forms including non-crystalline glass and noncrystalline amorphous forms.
  • the invention does not intend to encompass within the scope of the invention any previously disclosed product, process of making the product or method of using the product, which meets the written description and enablement requirements of the USPTO (35 U.S.C. 1 12, first paragraph) or the EPO (Article 83 of the EPC), such that applicant(s) reserve the right and hereby disclose a disclaimer of any previously described product, method of making the product or process of using the product.
  • the compounds may be combined with one or more additional active agents in compositions to broaden the scope of coverage against both endoparasites and ectoparasites.
  • substituted with reference to a chemical formula means that one or more of the hydrogen atoms on the compound or functional group is replaced with the substituent described.
  • animal is used herein to include all mammals, birds and fish and also include all vertebrate animals.
  • Animals include, but are not limited to, cats, dogs, cattle, chickens, cows, deer, goats, horses, llamas, pigs, sheep and yaks. It also includes an individual animal in all stages of development, including embryonic and fetal stages. In some embodiments, the animal will be a non-human animal.
  • active agent or “active ingredient” or “therapeutic agent” as used in this specification, means an anthelmintic compound of the invention.
  • fatty acid refers to carboxylic acids having from 4 to 26 carbon atoms.
  • fatty alcohol or "long-chain aliphatic alcohol” refer to aliphatic alcohols containing from 6 to 20 carbon atoms.
  • alkyl refers to saturated straight, branched, cyclic, primary, secondary or tertiary hydrocarbons, including those having 1 to 20 atoms.
  • alkyl groups will include C1-C12, C1-C10, Ci-Cs, C1-C6 or C1-C4 alkyl groups.
  • C1-C10 alkyl examples include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1- methylpropyl, 2-methylpropyl, 1 , 1 -dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3- methylbutyl, 2,2-dimethylpropyl, 1 -ethylpropyl, hexyl, 1, 1-dimethylpropyl, 1,2- dimethylpropyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1- dimethylbutyl, 1 ,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1, 1,2-trimethylpropyl, 1,
  • Carbocyclyl refers to carbon-containing ring systems, including both “cycloalkyl” and “aryl” groups as defined herein.
  • Cyclic alkyl groups or "cycloalkyl", which are encompassed by alkyl include those with 3 to 10 carbon atoms having single or multiple condensed rings.
  • cycloalkyl groups include C4-C7 or C3-C4 cyclic alkyl groups.
  • Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • alkyl groups described herein can be unsubstituted or substituted with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkyl, carboxyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, acyl, acyloxy, sulfanyl, sulfamonyl, amino, alkyl- or dialkylamino, amido, arylamino, alkoxy, haloalkoxy, aryloxy, nitro, cyano, azido, thiol, imino, sulfonic
  • alkyl such as “alkylcycloalkyl,” “cycloalkylalkyl,” “alkylamino,” or “dialkylamino” will be understood to comprise an alkyl group as defined above linked to the other functional group, where the group is linked to the compound through the last group listed, as understood by those of skill in the art.
  • alkenyl refers to both straight and branched carbon chains which have at least one carbon-carbon double bond.
  • alkenyl groups may include C2-C20 alkenyl groups.
  • alkenyl includes C 2 -C 12 , C2-C10, C2-C8, C2-C6 or C2-C4 alkenyl groups.
  • the number of double bonds is 1-3, in another embodiment of alkenyl, the number of double bonds is one or two. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated depending on the location of the alkenyl moiety on the molecule.
  • “C2-Cio-alkenyl” groups may include more than one double bond in the chain.
  • Examples include, but are not limited to, ethenyl, 1- propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 -methyl- 1- propenyl, 2-methyl-l-propenyl, 1 -methyl-2-propenyl, 2-methyl-2-propenyl; 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 1 -methyl- 1-butenyl, 2-methyl- 1 -butenyl, 3 -methyl- 1- butenyl, 1-methy 1-2 -butenyl, 2-methyl-2-butenyl, 3 -methy 1-2 -butenyl, l-methyl-3 -butenyl, 2- methyl-3 -butenyl, 3 -methyl-3 -butenyl, l,l-dimethyl-2-propenyl, 1,2-dimethyl-l-propenyl,
  • alkynyl refers to both straight and branched carbon chains which have at least one carbon-carbon triple bond.
  • the number of triple bonds is 1-3; in another embodiment of alkynyl, the number of triple bonds is one or two.
  • alkynyl groups include from C2-C2 0 alkynyl groups. In other embodiments, alkynyl groups may include C 2 -C 12 , C2-C1 0 , C2-C8, C2-C6 or C2-C4 alkynyl groups. Other ranges of carbon-carbon triple bonds and carbon numbers are also contemplated depending on the location of the alkenyl moiety on the molecule.
  • C2-C1 0 - alkynyl refers to a straight-chain or branched unsaturated hydrocarbon group having 2 to 10 carbon atoms and containing at least one triple bond, such as ethynyl, prop-1- yn- 1 -yl, prop-2-yn- 1 -yl, n-but- 1 -yn- 1 -yl, n-but- 1 -yn-3 -yl, n-but- 1 -yn-4-yl, n-but-2-yn- 1 -yl, n- pent-l-yn-l-yl, n-pent-l-yn-3-yl, n-pent-l-yn-4-yl, n-pent-l-yn-5-yl, n-pent-2-yn-l-yl, n- pent-2-yn-4-yl, n-pent-2-yn-yl, n- pent
  • haloalkyl refers to an alkyl group, as defined herein, which is substituted by one or more halogen atoms.
  • Ci-C4-haloalkyl includes, but is not limited to, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1- chloroethyl, 1 -bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and the like.
  • haloalkenyl refers to an alkenyl group, as defined herein, which is substituted by one or more halogen atoms.
  • haloalkynyl refers to an alkynyl group, as defined herein, which is substituted by one or more halogen atoms.
  • Ci-C6-alkoxy examples include, but are not limited to, methoxy, ethoxy, C2H5-CH2O-, (CH 3 ) 2 CHO-, n-butoxy, C2H5- CH(CH 3 )0-, (CH 3 ) 2 CH-CH 2 0-, (CH 3 ) 3 CO-, n-pentoxy, 1 -methylbutoxy, 2-methylbutoxy, 3- methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethyl-propoxy, 1- ethylpropoxy, n-hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4- methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2- dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy,
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkylthio refers to haloalkyl-S- and cycloalkyl- S- where haloalkyl and cycloalkyl are as defined above.
  • halothio refers to (halogen)5-S-, wherein halogen is as defined above.
  • An example of “halothio” is the group F 5 S-.
  • alkylsulfinyl refers to alkyl-S(O)-, wherein alkyl is as defined above.
  • haloalkylsulfinyl refers to haloalkyl-S(O)- where haloalkyl is as defined above.
  • alkylsulfonyl refers to alkyl-S(0)2-, wherein alkyl is as defined above.
  • haloalkylsulfonyl refers to haloalkyl-S(0)2- where haloalkyl is as defined above.
  • alkylamino and dialkylamino refer to alkyl-NH- and (alkyl ⁇ N- where alkyl is as defined above.
  • haloalkylamino refers to haloalkyl-NH- where haloalkyl is as defined above.
  • alkylcarbonyl alkoxycarbonyl
  • alkylaminocarbonyl alkylaminocarbonyl
  • dialkylaminocarbonyl refer to alkyl-C(O)-, alkoxy-C(O)-, alkylamino-C(O)- and dialkylamino-C(O)- where alkyl, alkoxy, alkylamino and dialkylamino are as defined above.
  • haloalkylcarbonyl refers to the groups haloalkyl-C(O)-, haloalkoxy-C(O)-, haloalkylamino-C(O)- and dihaloalkylamino-C(O)- where haloalkyl, haloalkoxy, haloalkylamino and dihaloalkylamino are as defined above.
  • Aryl refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings.
  • aryl groups include C 6 -Cio aryl groups.
  • Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, biphenylene, fluorene, anthracene, acenaphthene, phenanthrene and indanyl.
  • Examples of bicyclic aryl groups include naphthyl and indanyl.
  • Aryl groups may be unsubstituted or substituted by one or more moieties selected from halogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy, cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy, alkylthio, haloalkylthio, cycloalkylthio, halocycloalkylthio, alkylsulfinyl, alkenylsulfinyl, alky
  • aralkyl or "arylalkyl” refers to an aryl group that is bonded to the parent compound through a diradical alkylene bridge, (-CH 2 -) n , where n is 1-12 and where "aryl” is as defined above.
  • Heteroaryl refers to a monovalent aromatic group of from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, having one or more oxygen, nitrogen, and sulfur heteroatoms within the ring, preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings provided that the point of attachment is through a heteroaryl ring atom.
  • Preferred heteroaryls include pyridyl, piridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl, dihydrobenzofuranyl and benzothiophenyl.
  • Heteroaryl rings may be unsubstituted or substituted by one or more moieties as described for aryl above.
  • Heterocyclyl refers to fully saturated or unsaturated, cyclic groups, for example, including a 3 to 8 membered monocyclic, a 4 to 7 membered monocyclic and 5 to 6 membered monocyclic ring; 7 to 12 membered bicyclic; 10 to 15 membered tricyclic; or 6-12-membered spirocyclic ring systems, which have one or more oxygen, sulfur or nitrogen heteroatoms in ring, preferably 1 to 4 or 1 to 3 heteroatoms.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system and may be unsubstituted or substituted by one or more moieties as described for aryl groups above.
  • Exemplary monocyclic heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, 4-piperidonyl,
  • bicyclic heterocyclic groups include, but are not limited to, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benz[d]isoxazolyl, benzotriazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, dihydrobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, indazolyl, pyrrolopyridyl, phthalazinyl, 1,2,3-benzotriazinyl, 1,2,4- benzotriazinyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl
  • Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.
  • Halogen means the atoms fluorine, chlorine, bromine and iodine.
  • the designation of "halo" (e.g. as illustrated in the term haloalkyl) refers to all degrees of substitutions from a single substitution to a perhalo substitution (e.g. as illustrated with methyl as chloromethyl (- CH 2 C1), dichloromethyl (-CHCI2), trichloromethyl (-CCI3)).
  • an anthelmintic compound of Formula (I) is provided.
  • X 2 or X7 is a linker LI 9, L20 or L21 as defined herein or a spirocyclic carbocyclic ring linker, a heterocyclic ring linker comprising two heterocyclic rings or a carbocyclic -heterocyclic ring system joined at one carbon, wherein each ring of the spirocyclic linker contains 4, 5 or 6 ring atoms, and wherein each of LI 9, L20 or L21 or the spirocyclic ring linker is optionally independently substituted by one or more of halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, hydroxy, thiol, Ci-C6alkoxy, Ci-C6haloalkoxy or oxo; Y and Z are independently a bicyclic carbocyclic or a bicyclic heterocyclic group optionally independently substituted by one or more of halogen, nitro, cyano, hydroxy, hydroxyalkyl
  • haloalkylsulfinyl alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl or heteroarylalkylsulfonyl; or
  • one of Y or Z is a bicyclic carbocyclic or a bicyclic heterocyclic group optionally substituted by one or more of halogen, nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aminocarbonyl, alkyl- or dialkylaminocarbonyl, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfin
  • Xi is a bond, -0-, -C(O)-, -C(S)-, -NH-, -S, -S(O), -S(0) 2 -,-NHS(0)-, -S(0)-NH-, -NHSO2-, -SO2NH-, -(CH 2 ) n - where n is 1 to 3, -C(0)-CH 2 -, -CH 2 -C(0)-, -0-CH 2 -, -CH 2 -0- , -NHCH 2 -, -CH2- H-, -S-CH2-, -CH2-S-, -S(0)-CH 2 -, -CH 2 -S(0)-, -S(0) 2 -CH 2 -, or -CH 2 - S(0) 2 -, wherein each -NH-, -NHS(O)-, -S(0)-NH-, -NHS0 2 -, -S0 2 NH-, -(CH
  • alkylcarbonyl alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl or aryl groups, where each substituent group may be further substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH);
  • X 2 is a linker selected from a Ci-Cs-alkylene group, a C 2 -Cs-alkenylene group, a C 2 - Ce-alkynylene group, a 3-8 membered carbocyclylene and 3-8 membered heterocyclylene group or a spirocyclic carbocyclic ring liner, a spirocyclic heterocyclic ring linker comprising two heterocyclic ring systems or a spirocyclic carbocyclic -heterocyclic ring system joined at one carbon, where each ring of the spirocyclic system contains 4, 5 or 6 ring atoms, wherein the heterocyclylene group contains one to four nitrogen, oxygen or sulfur atoms, and wherein one to three of the carbon atoms in the Ci-Cs-alkylene group, the C 2 -Cs-alkenylene group and the C 2 -C8-alkynylene group may be replaced by a nitrogen, an oxygen or sulfur
  • X3 is a diradical group selected from the group consisting of a bond, -(CH 2 ) n - where n is 1 to 3, -0-, -C(S)-, -C(0)-, -S(0)-, -S(0)2-, and an oxetane group (4-membered ring containing one oxygen), wherein X2 and X 4 may be bonded to any carbon atom of the oxetane group; and wherein each -CH 2 - in the -(CH 2 ) n - group is optionally independently substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl and halocarbocyclyl;
  • X 4 is a bond, -(CH 2 ) n - where n is 1 to 3, carbocyclylene or heterocyclylene, wherein the -CH 2 -, the carbocyclylene and the heterocyclylene groups are optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl alkylaminoalkyl, dialkylaminoalkyl, alkyl or aryl sulfinyl, alkyl or arylsulfonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl and halocarbocyclyl;
  • X5 is absent or is a bond, -(CH2) n where n is 1 to 3, carbocyclylene or heterocyclylene, wherein each -CH 2 - in the -(CH 2 ) n group, the carbocyclylene and the heterocyclylene groups are optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl alkylaminoalkyl, dialkylaminoalkyl, alkyl or aryl sulfinyl, alkyl or arylsulfonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl and halocarbocyclyl;
  • X 6 is -(CH 2 ) n - where n is 1 to 3, -0-, -C(0)-, -C(S)-, -S-, -S(0)-, -S(0) 2 -, -NH-, -C(0)-NH-, -C(S)-NH-, -NH-C(O)-, -NH-C(S)-, wherein each -CH 2 - in the -(CH 2 ) n - group, -NH-, -C(0)-NH-, -C(S)-NH-, -NH-C(O)-, -NH-C(S)- are optionally independently substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl
  • alkylaminoalkyl dialkylaminoalkyl, alkyl or aryl sulfinyl, alkyl or arylsulfonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl,
  • X7 is a bond, -(CH 2 ) n - where n is 1 to 8, C 2 -C6-alkenylene, C 2 -C6-alkynylene, a 3-8- membered carbocyclylene, a 3-8-membered heterocyclylene containing one to four nitrogen, oxygen or sulfur atoms or a spirocyclic carbocyclic ring linker, a spirocyclic heterocyclic linker comprising two heterocyclic ring systems or a spirocyclic carbocyclic-heterocyclic ring system joined at one carbon, where each ring of the spirocyclic system contains 4, 5 or 6 ring atoms, wherein each CH 2 in -(CH 2 ) n - , the C2-C6-alkenylene, the C2-C6-alkynylene, the 3-8-membered carbocyclylene, the 3-8-membered heterocyclylene or the spirocycl
  • X 8 is a bond, -(CH 2 ) n - where n is 1 to 3, -0-, -C(0)-, -S-, -S(0)-, -S(0) 2 -, -NHS(O)-, -S(0)-NH-, -NHSO2-, -SO2NH- or -NH-, wherein each CH 2 in -(CH 2 ) n - , -NHS(O)-, -S(0)-NH-, -NHS0 2 -, -S0 2 NH- or -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, hydroxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbony
  • At least one of Y or Z is an optionally substituted bicyclic carbocyclic group. In another embodiment, at least one of Y or Z is an optionally substituted bicyclic aromatic carbocyclic group. In still another embodiment, at least one of Y or Z is an optionally substituted non-aromatic bicyclic carbocyclic group. In still another embodiment, at least one of Y or Z is optionally substituted naphthyl, tetrahydronaphthyl or indanyl.
  • At least one of Y or Z is a bicyclic heterocyclic group. In another embodiment, at least one of Y or Z is an optionally substituted bicyclic heteroaryl group. In still another embodiment, at least one of Y or Z is optionally substituted indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetra-hydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, dihydrobenzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3- c
  • X l is a bond, -C(O)-, -CH 2 -, -CH 2 CH 2 -, -C(0)-CH 2 -, -CH 2 -C(0), -0-CH 2 -, -CH 2 -0-, -NHCH 2 - or -CH 2 -NH-, wherein each -CH 2 -, -CH 2 CH 2 -, -C(0)CH 2 -, - CH 2 -C(0)-, -0-CH 2 -, -CH 2 -0, -NH-CH 2 , -CH 2 -NH- are optionally independently substituted with one or more halogen, alkyl, haloalkyl or cycloalkyl groups.
  • X l is -NH-, -NHS(O)-, -S(0)-NH-, -NHS0 2 - or -S0 2 NH-.
  • Xi is a bond, -CH 2 - or -CH2CH2-, wherein each -CH 2 - or -CH 2 CH 2 -is optionally independently substituted with one or more halogen, alkyl or haloalkyl groups.
  • Xi is -NH- is optionally substituted with a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
  • a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl,
  • X ⁇ is -NH- is optionally substituted with a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl or haloalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
  • a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl or haloalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy
  • the invention when the Xi moiety is a nitrogen-containing group, it may be utilized to attach groups that will convert to the unsubstituted -NH- group in vivo (e.g. a produg).
  • X 2 is a Ci-Cs-alkylene group, a 3-8 membered carbocyclylene, a 3-8 membered heterocyclylene group containing one to four nitrogen, oxygen or sulfur heteroatoms, or a spirocyclic carbocyclic ring linker, a spirocyclic heterocyclic linker comprising two heterocyclic ring systems or a spirocyclic carbocyclic -heterocyclic ring system joined at one carbon, where each ring of the spirocyclic system contains 4, 5 or 6 ring atoms, wherein one or more of the carbon atoms in the Ci-Cs-alkylene group may be replaced by a nitrogen, oxygen or sulfur atom; and wherein the Ci-Cs-alkylene group, the 3-8 membered carbocyclylene, the 3-8 membered heterocyclylene group or the spirocyclic linker group are optionally independently substituted with one or more substituents selected from halogen, al
  • X2 comprises a chain of from 3 to 6 atoms (as an acyclic chain or part of a ring) that bridges Xi to X 3 , wherein 1 or 2 of the chain atoms are nitrogen.
  • the nitrogen atoms in X2 are typically bonded to Xi and/or X 3 .
  • X2 is a 3-8 membered heterocyclylene group containing at least one nitrogen atom. In still another embodiment, X2 is a heterocyclylene group containing at least two nitrogen atoms. In yet another embodiment, X2 is a 5- or 6-membered heterocyclylene group containing one or two nitrogen atoms.
  • X2 is a 3 or 4-membered heterocyclylene linker with one ring nitrogen atom. In another embodiment, X2 is a 5 or 6-membered heterocyclylene linker with one or two ring nitrogen atoms. In still another embodiment, X2 is a bicyclic heterocyclylene linker containing one or two nitrogen atoms where each ring of bicyclic ring system has 4, 5 or 6 ring atoms.
  • X2 is a spirocyclic carbocyclic ring linker, a spirocyclic heterocyclic linker comprising two heterocyclic ring systems or a carbocyclic -heterocyclic ring system joined at one carbon, where each ring of the spirocyclic system contains 4, 5 or 6 ring atoms.
  • X2 and/or X7 are selected from one of the linkers LI to L21 in Table 1 below, wherein variables R and R' are each independently hydrogen, alkyl, haloalkyl or arylalkyl; R2 and R 3 are independently hydrogen, halogen, cyano, alkyl, haloalkyl or carbocyclyl; R4 is H, OH, halogen or Ci_ 3 alkyl; R 5 , R 6 , R7 and Rs are independently hydrogen, Ci_ 3 alkyl or Ci_ 3 haloalkyl; W and W are each independently O or S; and each linker LI to L21 in the table may be independently substituted by one or more of halogen, cyano, Ci-C 6 alkyl, hydroxy, thiol, Ci-C 6 alkoxy, oxo or thiocarbonyl.
  • the X2 and X7 linkers presented in Table 1 may be bonded to Xi and/or X3 or X and/or Xs at any possible atom in the linker group.
  • the nitrogen atom(s) will be bonded to Xi and/or X 3 or X 6 and/or X 8 .
  • X2 and/or X7 is LI . In another preferred embodiment, X2 and/or X7 is L2. In yet another preferred embodiment, X2 and/or X7 is LI 1 or L12. In another embodiment, X2 and/or X7 is L13 or LI 4. In still another embodiment, X2 and/or X7 is LI 3 where the 3 ⁇ 4 and R7 groups are in a iraws-relationship to each other. In yet another embodiment, X2 and/or X7 are L13 where the Re and R7 groups are in a cis-relationship to each other. In another embodiment, X2 and/or X7 are L 14 where the Re and R7 groups are in a trans-relationship to each other.
  • X2 and/or X7 are L14 where the R6 and R7 are in a cis-relationship to each other. In yet another embodiment, X2 and/or X7 are L15 where the R6 and R7 are trans to each other. In still another embodiment, X2 and/or X7 are L15 where R6 and R7 are cis- to each other. In still another embodiment, X2 and/or X7 are LI 6, LI 7 or LI 8. In another embodiment, X2 and/or X7 are LI 9, L20 or L21.
  • X3 is a bond, -(CH 2 ) n - where n is 1 to 3, -C(S)- or -C(O)-, wherein each carbon atom in the -(CH 2 ) n - group is optionally independently substituted with one or two substituents selected from the group consisting of halogen, alkyl or haloalkyl.
  • X 3 is -C(O)-.
  • X 3 is -CH 2 CH 2 - or -CH 2 CH 2 CH 2 - wherein each of the carbon atoms may be substituted by one or two methyl groups.
  • X3 is an oxetane group.
  • X 4 is a bond. In another embodiment, X 4 is -(CH 2 ) n - where n is 1 or 2, wherein each -CH 2 - is optionally independently substituted with one or two substituents selected from the group consisting of halogen, alkyl, haloalkyl and carbocyclyl;
  • X5 is a bond or -(CED n - where n is 1 or 2 and wherein each -CH 2 - in the -(CH 2 ) n group is optionally independently substituted with one or two halogen, alkyl, haloalkyl, or carbocyclyl groups;
  • X 6 is -(CH 2 ) n where n is 1 or 2, -0-, -C(O)-, -S-, -S(O)-, -S(0) 2 - or -NH-, wherein each -CH 2 - in the -(CH 2 ) n - group or the NH, is optionally independently substituted with one or two substituents is selected from the group consisting of halogen, alkyl, haloalkyl and carbocyclyl.
  • X 6 is CH 2 .
  • X 6 is -0-.
  • X 7 is a bond, -(CH 2 ) n - where n is 1 to 3, carbocyclylene or heterocyclylene, wherein each CH2 in -(CED n -, carbocyclylene and heterocyclylene is optionally independently substituted with one or more halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, alkylamino or dialkylamino or aminoalkyl.
  • X 7 is a 5- or 6-membered carbocyclylene group such as cyclohexylene or cyclopentylene.
  • X7 is a phenylene group.
  • X7 is a 3 or 4-membered heterocyclylene linker with one ring nitrogen atom. In another embodiment, X7 is a 5 or 6-membered heterocyclylene linker with one or two ring nitrogen atoms. In still another embodiment, X7 is a bicyclic heterocyclylene linker containing one or two nitrogen atoms where each ring of bicyclic ring system has 4, 5 or 6 ring atoms.
  • X7 is a spirocyclic carbocyclic ring linker, a spirocyclic heterocyclic linker comprising two heterocyclic ring systems or a carbocyclic- heterocyclic ring system joined at one carbon, where each ring of the spirocyclic system contains 4, 5 or 6 ring atoms.
  • X 8 is absent or is a bond, -(CH 2 ) n where n is 1 to 3, -0-, -C(O)- or -NH-, wherein each CH 2 in -(CH 2 ) n - and the -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, alkyl, and haloalkyl.
  • Xs is -NH-.
  • Xs is -C(O)-.
  • X 8 is -CH 2 -, -CF 2 -, -CH(CH 3 )- or - C(CH 3 ) 2 -.
  • X 8 is -NHS(O)-, -S(0)-NH-, -NHS0 2 - or -S0 2 NH-.
  • Xs is -NH- is optionally substituted with a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (- COOH).
  • a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl,
  • X 8 is -NH- which is optionally substituted with a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl and haloalkyl, where the substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
  • a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl and haloalkyl, where the substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy
  • the Xs moiety when the Xs moiety is a nitrogen-containing group, it may be utilized to attach groups that will convert to the unsubstituted -NH- group in vivo (e.g. a produg).
  • the compounds of formula (I) have the structure (IA) shown below:
  • Ring A and Ring B are independently a 3 to 8-membered monocyclic or a 7 to 1 1-membered bicyclic carbocyclylene or heterocyclylene ring, or a spirocyclic carbocyclic ring linker, a spirocyclic heterocyclic linker comprising two heterocyclic ring systems or a carbocyclic -heterocyclic ring system joined at one carbon, where each ring of the spirocyclic system contains 4, 5 or 6 ring atoms, wherein one or more of the carbon atoms in the Ci-Cs-alkylene group may be replaced by a nitrogen, oxygen or sulfur atom, wherein the heterocyclic ring contains 1 to 4 heteroatoms selected from N, O and S; and the Linker is the segment -X 3 -X4-X5-X6- where X 3 , X 4 , X5 and Xe
  • Ring A is one of LI to L10, L13 to L18 or L19 to L21 as defined in Table 1, which may optionally be substituted with halogen, alkyl or haloalkyl.
  • Ring A is cyclohexylene or phenylene, which may optionally be substituted with halogen, alkyl or haloalkyl.
  • Ring B is cyclohexylene or phenylene, which may optionally be substituted with halogen, alkyl or haloalkyl.
  • Ring B is one of LI to L10, L13 to LI 8 or LI 9 to L21 as defined in Table 1, which may optionally be substituted with halogen, alkyl or haloalkyl.
  • Xi is a bond, an optionally substituted -(CH 2 ) n - where n is 1 to 3, or -C(O)-.
  • X 8 is -C(O)-, -NH- or -(CH 2 ) n - where n is 1 to 3, wherein the each CH 2 in -(CH 2 ) n - or the -NH- may optionally be substituted.
  • Y and/or Z is phenyl or naphthyl optionally substituted with one or more of halogen, nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylalk
  • Y and/or Z are independently phenyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted by one or more halogen, nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfon
  • the compound has the structure of formula IA- 1) or (IA-2) shown below:
  • Ring A is a 3- to 8-membered or 5- to 6-membered carbocyclic or heterocyclic ring where Q5 and (3 ⁇ 4 are independently N, C or CR4 where R4 is H, OH, halogen or each Q 4 is a ring nitrogen, oxygen or sulfur or a substituent 3 ⁇ 4; W is O, S or an oxetane group (-CH 2 OCH 2 -);
  • Ring B is a 3- to 8-membered monocyclic carbocyclic or heterocyclic ring, a 7-12-membered bicyclic carbocyclic or heterocyclic ring, or a spirocyclic carbocyclic ring linker, a spirocyclic heterocyclic ring system comprising two heterocyclic rings or a carbocyclic- heterocyclic ring system joined at one carbon, wherein each ring of the spir
  • W is O. In another embodiment, W is an oxetane group. In another embodiment, Ring B is optionally substituted phenylene.
  • Ring A is one of linkers LI, L2,
  • Ring A is one of LI, L13, L14 or L15.
  • Ring A is L16, L17 or L18.
  • Ring A is LI 9, L20 or L21.
  • Ring A is L4, L5, L6, L7, L9 or L10.
  • Ring B is LI, L13, L14 or L15.
  • Ring B is LI 9, L20 or L21.
  • Ring A and Ring B are each independently one of LI, L2, L3, L8, L13, L14, L15, L16, L17, L18, L19, L20 or L21.
  • Y and/or Z are naphthyl optionally substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
  • Y and/or Z are independently benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which are optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkyl
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkyl
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 ; and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl.
  • X l is -NH-, -NHS(O)-, -S(0)-NH-, -NHS0 2 - or -S0 2 NH-.
  • Xi is a bond, -CH 2 - or -CH 2 CH 2 -, wherein each -CH 2 - or -CH 2 CH 2 -is optionally independently substituted with one or more halogen, alkyl or haloalkyl groups.
  • Xi is -NH- which is optionally substituted a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
  • a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl,
  • Xi is -NH- which is optionally substituted with a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl and haloalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
  • a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl and haloalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy
  • X 8 is -NH-, -NHS(O)-, -S(0)-NH-, -NHS0 2 - or -S0 2 NH-.
  • X 8 is a bond, -CH 2 - or -CH 2 CH 2 -, wherein each -CH 2 - or -CH 2 CH 2 -is optionally substituted with one or more halogen, alkyl or haloalkyl groups.
  • Xs is -NH- which is optionally substituted with a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (- COOH).
  • a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl
  • X 8 is -NH- is optionally substituted with a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl and haloalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
  • a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl and haloalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (
  • Xi is optionally substituted -(CH 2 ) n - or -C(O)-.
  • X 8 is -C(O)- or optionally substituted -NH- or -(CH 2 ) n -.
  • R2 and R 3 are H.
  • one or both of R2 and R 3 are methyl.
  • n is 1 or 2.
  • X is -0-, -NH- which may optionally be substituted by alkyl or haloalkyl; -S-, -S(O)- or -S(0) 2 -.
  • Xi is a bond, -C(O)- or -CH 2 -; W is O, Xe is -0-, n is 0, 1 or 2, R 2 and R 3 are H and m and q are 0.
  • Q3 is a ring nitrogen and q is 1. In another embodiment, Q3 is a ring nitrogen and q is 2. In another embodiment, Q 4 is a ring nitrogen and m is 1. In yet another embodiment, Q 4 is a ring nitrogen and m is 2.
  • Q 2 and Q5 are N. In another embodiment, Q5 and (3 ⁇ 4 are N and Qi
  • Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, Ci- 3 alkyl, Ci- 3 haloalkyl, phenyl, hydroxy, Ci- 3 hydroxyalkyl, amino, Ci- 3 alkyl- or Ci- 3 dialkylamino, Ci- 3 alkoxy, Ci- 3 haloalkoxy, C h alky lthio, halothio, Ci- 3 haloalkylthio, C 1-3 alky lsulf
  • Ring A is one of LI , L2, L3, L4, L5, L6, L7, L8, L9, L10, L13, L14, L15, L16, L17, LI 8, LI 9, L20 or L21 shown in Table 1 ;
  • W is O, S or an oxetane group
  • R 2 and R 3 are independently H, halogen, Ci-C 3 alkyl or Ci-C 3 haloalkyl;
  • X 6 is a bond, -(CH 2 ) n - where n is 1 to 3, -0-, -NH-, -C(0)-NH- and -NH-C(O)-, wherein each -CH 2 - in the -(CH 2 ) n - group, -NH-, -C(0)-NH- and -NH-C(O)- are optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, Ci ⁇ hydroxyalkyl, amino, Ci- 3 alkylamino, Ci- 3 dialkylamino, Ci- 3 aminoalkyl, Ci- 3 alkyl and Ci- 3 haloalkyl;
  • X 8 is a bond, -(CH 2 ) n where n is 1 to 3, -0-, -C(O)-, -S-, -S(O)-, -S(0) 2 -, -NHS(O)-, - S(0)-NH-, -NHSO 2 -, -SO 2 NH- or -NH-, wherein each CH 2 in -(CH 2 ) n - , -NHS(O)-, -S(O)- NH-, -NHSO 2 -, -SO 2 NH- or -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, hydroxy, amino, Ci- 3 alkylamino, Ci- 3 dialkylamino, Ci- 3 hydroxyalkyl, Ci- 3 aminoalkyl, Ci- 3 alkyl, Ci- 3 haloalkyl and Ci- 3 alkoxyalkyl;
  • Qi and Q 2 are each independently C-H or N;
  • Q3 is C-H or a ring nitrogen
  • Ring A is one of LI 9, L20 or L21 ;
  • Ring B is a optionally substituted cyclohexylene or phenylene, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfiny
  • Ring A is a optionally substituted cyclohexylene or phenylene
  • Ring B is one of LI 9, L20 or L21
  • Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl
  • Ring A and Ring B are each independently one of LI, L2, L3, L4, L5, L6, L7, L8, L9, LIO, L13, L14, L15, L16, L17, L18, L19, L20 or L21 ;
  • Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalky
  • Ring A is one of LI 9, L20 or L21 ;
  • Ring B is an optionally substituted diradical pyridine ring linker where Q 3 is a ring nitrogen, Qi and Q 2 are C and q is 1 ,
  • Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, al
  • Ring A is an optionally substituted diradical pyridine ring linker where Q 4 is a ring nitrogen, Q5 and (3 ⁇ 4 are C and m is 1 , Ring B is one of L19, L20 or L21 ; Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio
  • Ring A is LI 9, L20 or L21 ;
  • Ring B is a optionally substituted cyclohexylene or phenylene, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,
  • Ring A and Ring B are each independently one of LI, L2, L3, L4, L5, L6, L7, L8, L13, L14, L15, L16, L17, L18, L19, L20 or L21 ;
  • Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alky
  • Ring A is optionally substituted cyclohexylene or phenylene
  • Ring B is L19, L20 or L21
  • Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,
  • Ring A is L19, L20 or L21 ;
  • Ring B is a optionally substituted cyclohexylene or phenylene, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl
  • Ring A is L19, L20 or L21 ;
  • Ring B is a optionally substituted cyclohexylene or phenylene, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl
  • Ring A is L19, L20 or L21 ;
  • Ring B is a optionally substituted cyclohexylene or phenylene, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl
  • Ring A and Ring B are each independently one of LI, L2, L3, L4, L5, L6, L7, L8, L13, L14, L15, L16, L17, L18, L19, L20 or L21 ;
  • Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alky
  • Ring A and Ring B are each independently one of LI, L2, L3, L4, L5, L6, L7, L8, L13, L14, L15, L16, L17, L18, L19, L20 or L21 ;
  • Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alky
  • Ring A and Ring B are each independently one of LI, L2, L3, L4, L5, L6, L7, L8, L13, L14, L15, L16, L17, L18, L19, L20 or L21 ;
  • Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alky
  • Ring A is a optionally substituted cyclohexylene or phenylene
  • Ring B is L19, L20 or L21
  • Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,
  • Ring A is a optionally substituted cyclohexylene or phenylene
  • Ring B is L19, L20 or L21
  • Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,
  • Ring A is a optionally substituted cyclohexylene or phenylene
  • Ring B is L19, L20 or L21
  • Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3; SCF 3 or SF 5 ; and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl; Ring A is one of LI 9, L20 or L21
  • Ring B is trans-cyclohexylene or phenylene
  • W is O
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-, wherein each CH 2 in -(CH 2 ) n - and -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, Ci- 3 alkyl, Ci- 3 haloalkyl, hydroxy-C 1-3 alky 1, Ci- 3 alkoxy-Ci- 3 alkyl, amino-Ci- 3 alkyl, Ci- 3 alkylamino-Ci- 3 alkyl, Ci- 3 dialkylamino-Ci- 3 alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl and C 2 -4alkenylcarbonyl, each of which may be further substituted by hydroxy, hydroxy-C 1-3 alky 1, amino, C h alky lamino, Ci- 3 dialkylamino or carboxy (-COOH);
  • R 2 and R3 are H; n is 1 or 2; and m and q are 0.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3; SCF 3 or SF 5 ; and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • Xi is a bond, -C(O)-, -(CH 2 ) n - where n is 1 to 3 or -NH-, wherein each CH 2 in -(CH 2 ) n - and -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, Ci- 3 alkyl, Ci- 3 haloalkyl, hydroxy-Ci- 3 alkyl, Ci- 3 alkoxy-Ci- 3 alkyl, amino-Ci- 3 alkyl, Ci- 3 alkylamino-Ci- 3 alkyl, Ci- 3 dialkylamino-Ci- 3 alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl and C 2 -4alkenylcarbonyl, each of which may be further substituted by hydroxy, hydroxy-C 1-3 alky 1, amino, C h alky lamino, Ci- 3 dialkylamino or carboxy (-COOH);
  • Ring A is trans-cyclohexylene or phenylene
  • Ring B is one of LI 9, L20 or L21 ;
  • W is O
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-, wherein each CH 2 in -(CH 2 ) n - and -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, Ci- 3 alkyl, Ci- 3 haloalkyl, hydroxy-C 1-3 alky 1, Ci- 3 alkoxy-Ci- 3 alkyl, amino-Ci- 3 alkyl, Ci- 3 alkylamino-Ci- 3 alkyl, Ci- 3 dialkylamino-Ci- 3 alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl and C 2 -4alkenylcarbonyl, each of which may be further substituted by hydroxy, hydroxy-C 1-3 alky 1, amino, Ci- 3 alkylamino, Ci- 3 dialkylamino or carboxy (-COOH);
  • R2 and R 3 are H; n is 1 or 2; and m and q are 0.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3; SCF 3 or SF 5 ; and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • Xi is a bond, -C(O)-, -(CH 2 ) n - where n is 1 to 3 or -NH-, wherein each CH 2 in
  • -(CH 2 ) n - and -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, Ci- 3 alkyl, Ci- 3 haloalkyl, hydroxy-Ci- 3 alkyl, Ci- 3 alkoxy-Ci- 3 alkyl, amino-Ci- 3 alkyl, Ci- 3 alkylamino-Ci- 3 alkyl, Ci- 3 dialkylamino-Ci- 3 alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl and C 2 -4alkenylcarbonyl, each of which may be further independently substituted by hydroxy, hydroxy-Ci- 3 alkyl, amino, Ci- 3 alkylamino, Ci- 3 dialkylamino or carboxy (-COOH);
  • each of Ring A and Ring B is independently one of LI, L2, L3, L4, L5, LI 3, LI 4, L15, L16, L17, L18, L19, L20 or L21 ;
  • W is O
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-, wherein each CH 2 in -(CH 2 ) n - and -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, Ci- 3 alkyl, Ci- 3 haloalkyl, hydroxy-C 1-3 alky 1, Ci- 3 alkoxy-Ci- 3 alkyl, amino-Ci- 3 alkyl, Ci- 3 alkylamino-Ci- 3 alkyl, Ci- 3 dialkylamino-Ci- 3 alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl and C 2 -4alkenylcarbonyl, each of which may be further independently substituted by hydroxy, hydroxy-Ci- 3 alkyl, amino, Ci- 3 alkylamino, Ci- 3 dialkylamino or carboxy (-COOH);
  • R 2 and R 3 are H; n is 1 or 2; and m and q are 0.
  • the invention provides compounds formula (IA- 1) shown in Table 2 below, wherein W is O; R 2 and R 3 are H; n is 1 and variables Y, Xi, Xe, Xs, Z and Ring A and Ring B (which include variables Qi, Q 2 , Q3, Q 4 , Q5, (3 ⁇ 4, m and q) are described:
  • Table 2 Compounds of formula (IA-1) where W is O; R2 and R3 are H; n is 1; and B represents a bond.
  • the invention provides compounds of (IA-2) in which at least one of Ring A or Ring B is LI 9, L20 or L21 or a spirocyclic carbocyclic ring linker, a spirocyclic heterocyclic ring linker comprising two heterocyclic rings or a carbocyclic -heterocyclic ring system joined at one carbon, wherein each ring of the spirocyclic linker contains 4, 5 or 6 ring atoms.
  • W is O. In another embodiment, W is an oxetane group.
  • Ring A is one of the linkers LI, L2, L3, L4, L5, L6, L7, L8, L9, L10, L13, L14, L15, L16, L17, L18, L19, L20 or L21. In another embodiment, Ring A is one of LI, L2, L3, L8, L13, L14, L15, L16, L17, L18, L19, L20 or L21. In another embodiment, Ring A is LI, L13, L14 or L15. In yet another embodiment, Ring A is LI 6, LI 7, LI 8, LI 9, L20 or L21. In another embodimenty, Ring A is LI 9, L20 or L21.
  • Ring B is one of the linkers LI, L2, L3, L4, L5, L6, L7, L8, L9, L10, L13, L14, L15, L16, L17, L18, L19, L20 or L21.
  • Ring B is one of LI, L2, L3, L8, L13, L14, L15, L16, L17, L18, L19, L20 or L21.
  • Ring B is LI, L13, L14 or L15.
  • Ring B is L16, L17, L18, L19, L20 or L21.
  • Ring B is L19, L20 or L21.
  • Y and/or Z are naphthyl optionally independently substituted with one or more of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
  • Y and/or Z are independently benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkyls
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkyl
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 ; and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl.
  • Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, Ci- 3 alkyl, Ci- 3 haloalkyl, phenyl, hydroxy, Ci- 3 hydroxyalkyl, amino, Ci- 3 alkyl- or Ci- 3 dialkylamino, Ci- 3 alkoxy, Ci- 3 haloalkoxy, Ci- 3 alkylthio, Ci- 3 haloalkylthio, Ci- 3 alkylsulfinyl, Ci- 3
  • Ring A is one of the linkers LI, L2, L3, L4, L5, L6, L7, L8, L9, L10, L13, L14, L15, L16, L17, L18, L19, L20 or L21;
  • Xi is a bond, -C(O)-, -(CH 2 ) n - where n is 1 to 3, -0-CH 2 -, -NHCH 2 -, -S-CH 2 -, -S(O)-
  • W is O, S or an oxetane group
  • R2 and R 3 are independently H, halogen, Ci-C 3 alkyl or Ci-Cshaloalkyl;
  • X 8 is a bond, -(CH 2 ) n where n is 1 to 3, -0-, -C(O)-, -S-, -S(O)-, -S(0) 2 -, -NHS(O)-, - S(0)-NH-, -NHSO2-, -SO2NH- or -NH-, wherein each CH 2 in -(CH 2 ) n - , -NHS(O)-, -S(O)- NH-, -NHSO2-, -SO2NH- or -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, hydroxy, amino, alkylamino, dialkylamino, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl and alkoxy
  • Xi is -NH- in which the hydrogen is optionally replaced with a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, where each substituent may be further substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
  • a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, where each substituent may be further substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy
  • X 8 is NH- in which the hydrogen is optionally replaced with a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH) groups.
  • a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino
  • Xi is optionally substituted -(CH 2 ) n - or -C(O)-.
  • X 8 is -C(O)- or optionally substituted -NH- or -(CH 2 ) n -.
  • R 2 and R 3 are H.
  • n is 1 or 2.
  • Xi is a bond, -C(O)- or -CH2-; W is O, n is 1 or 2, R2 and R 3 are H and m and q are 0.
  • Y and/or Z are independently naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted with one or more halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl;
  • Xi is bond, -C(O)- or -CH 2
  • the invention provides the compounds of formula (IA-2) in Table 3 below, wherein Y, Xi, R 2 , R 3 , n, W, Xs, Z and Ring A and Ring B (which include variables Qi, Q 2 , Q 3 , Q 4 , Q5, Qe, m and q):
  • Ring B is independently a 3- to 8-membered carbocyclylene or heterocyclylene ring with 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen; a 7- to 12-membered bicyclic carbocyclylene or heterocyclylene ring containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; a spirocyclic carbocyclic ring linker, a spirocyclic heterocyclic ring linker comprising two heterocyclic rings or a carbocyclic -heterocyclic ring system joined at one carbon, wherein each ring of the spirocyclic linker contains 4, 5 or 6 ring atoms; or one of LI to L10 or L13 to L21 ; and the Linker is the segment X1-X2-X3-X4-X5-X6- where Xi, X 2 , X3, X 4 , X5 and Xe are as defined for
  • variables X 4 and/or X5 in the Linker segment Xi- X2-X3-X4-X5-X6- are absent.
  • Ring B is one of L19 to L21 as defined in Table 1, which may optionally be substituted with halogen, alkyl or haloalkyl.
  • Y and/or Z is naphthyl optionally substituted with one or more of halogen, nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroaryl
  • Y and/or Z are independently benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted by one or more of halogen, nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,
  • Y and/or Z are independently benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl each of which is optionally independently substituted by one or more halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfony
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl.
  • W is O. In another embodiment, W is an oxetane group. In yet another embodiment, the ring is an optionally substituted phenylene group. In yet another embodiment, X is -NH- in which the hydrogen may be replaced by alkyl, haloalkyl or arylalkyl, -0-, -S-, -S(O)- or -S(0)2-. In another embodiment, X 6 is - (CH2)n- optionally substituted by halogen, alkyl or haloalkyl. In still another embodiment of formula (IB-1), I3 ⁇ 4 and R 3 are H. In still another embodiment of formula (IB- 1), n is 1 or 2. In another embodiment of formula (IB- 1), X is -O- or -NH- which may optionally be substituted by alkyl or haloalkyl or arylalkyl.
  • Xs is a bond, -CH2- or -CH2CH2-, wherein each -CH2- or -CH 2 CH 2 -is optionally independently substituted with one or more halogen, alkyl or haloalkyl groups.
  • Xs is -NH- in which the hydrogen is optionally replaced with a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
  • a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbon
  • Xs is -NH- in which the hydrogen is optionally replaced with a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl and haloalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (- COOH).
  • a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl and haloalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or
  • Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted by one or more of halogen, nitro, cyano, SF 5 , alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkyls
  • W is O, S or an oxetane group
  • R2 and R3 are independently H, halogen, Ci-C 3 alkyl or Ci-Cshaloalkyl;
  • X 6 is a bond, -(CH 2 ) n - where n is 1 to 3, -0-, -NH-, -C(0)-NH- and -NH-C(O)-, wherein each -CH 2 - in the -(CH 2 ) n - group, -NH-, -C(0)-NH- and -NH-C(O)- are optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl and haloalkyl;
  • X 8 is is a bond, -(CH 2 ) n where n is 1 to 3, -0-, -C(O)-, -S-, -S(O)-, -S(0) 2 -, -NHS(O)-, -S(0)-NH-, -NHS0 2 -, -S0 2 NH- or -NH-, wherein each CH 2 in -(CH 2 ) n - , -NHS(O)-, -S(O)- NH-, -NHS0 2 -, -S0 2 NH- or -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, hydroxy, amino, alkylamino, dialkylamino, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl
  • the ring is optionally subtituted by halogen, Ci- 3 alkyl or Ci- 3 haloalkyl; and n is 0, 1, 2 or 3.
  • Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by one or more of halogen, nitro, cyano, SF 5 , Ci- 3 alkyl, Ci- 3 haloalkyl, phenyl, hydroxy, Ci- 3 hydroxy alkyl, amino, Ci- 3 alkyl- or Ci- 3 dialkylamino, Ci- 3 alkoxy, Ci- 3 haloalkoxy, C h alky lthio, Ci- 3 haloalkylthio, C 1-3 alky lsulfin
  • W is O, S or an oxetane group
  • R2 and R 3 are independently H, halogen, Ci-C 3 alkyl or Ci-C 3 haloalkyl;
  • X 6 is a bond, -(CH 2 ) n - where n is 1 to 3, -0-, -NH-, -C(0)-NH- and -NH-C(O)-, wherein each -CH 2 - in the -(CH 2 ) n - group, -NH-, -C(0)-NH- and -NH-C(O)- are optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, Ci ⁇ hydroxyalkyl, amino, Ci- 3 alkylamino, Ci- 3 dialkylamino, Ci- 3 aminoalkyl, Ci- 3 alkyl and Ci- 3 haloalkyl;
  • X 8 is is a bond, -(CH 2 ) n where n is 1 to 3, -0-, -C(O)-, -S-, -S(O)-, -S(0) 2 -, -NHS(O)-,
  • n 0, 1, 2 or 3.
  • W is O
  • Xe is -0-
  • Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted with one or more halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl,
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is optionally substituted by halogen, Ci- 3 alkyl or Ci- 3 haloalkyl; W is O; Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-;
  • R2 and R 3 are H;
  • n 1 or 2.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L19 optionally substituted by halogen, Ci- 3 alkyl or Ci- 3 haloalkyl;
  • W is O;
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-;
  • R2 and R 3 are H;
  • n 1 or 2.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L20 optionally substituted by halogen, Ci- 3 alkyl or Ci- 3 haloalkyl;
  • W is O;
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-;
  • R 2 and R 3 are H;
  • n 1 or 2.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L21 optionally substituted by halogen, Ci- 3 alkyl or Ci- 3 haloalkyl;
  • W is O;
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-;
  • R2 and R 3 are H;
  • n 1 or 2.
  • the ring is L19 optionally substituted by halogen, Ci- 3 alkyl or Ci- 3 haloalkyl; W is O, Y and/or Z are independently optionally substituted naphthyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, Xe is -0-, n is 1 or 2, R 2 and R 3 are H; and Xs is -NH-, -C(O)-, -CH 2 -, -CF 2 -, -CH(CH 3 )- or -C(CH 3 ) 2 -.
  • the ring is L20, W is O, Y and/or Z are independently optionally substituted naphthyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, Xe is -0-, n is 1 or 2, R 2 and R 3 are H; and X 8 is -NH-, -C(O)-, -CH2-, -CF2-, -CH(CH 3 )- or -C(CH 3 ) 2 -.
  • the ring is L21 , W is O, Y and/or Z are independently optionally substituted naphthyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, Xe is -0-, n is 1 or 2, R 2 and R 3 are H; and X 8 is -NH-, -C(0)-, -CH2-, -CF2-, -CH(CH 3 )- or -C(CH 3 ) 2 -.
  • W is O.
  • Xi is -0-, -S-, or -NH- in which the hydrogen atom may be replaced with alkyl, haloalkyl or arylalkyl.
  • X is -NH- in which the hydrogen may be replaced by alkyl, haloalkyl or arylalkyl; -0-, -S-, -S(0)- or -S(0) 2 -.
  • Xe is -(CH 2 )n- optionally substituted by halogen, alkyl or haloalkyl.
  • R 2 and R 3 are H.
  • n is 1 or 2.
  • W is O, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted with one or more halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that at least one
  • Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl
  • the ring is LI 9, L20 or L21 optionally substituted with halogen, Ci- 3 alkyl or Ci-
  • W is O, S or an oxetane group
  • R 2 and R3 are independently H, halogen, alkyl or haloalkyl
  • X 8 is a bond, -(CH 2 ) n where n is 1 to 3, -0-, -C(O)-, -S-, -S(O)-, -S(0) 2 -, -NHS(O)-, - S(0)-NH-, -NHS0 2 -, -S0 2 NH- or -NH-, wherein each CH 2 in -(CH 2 ) n - , -NHS(O)-, -S(O)- NH-, -NHS0 2 -, -S0 2 NH- or -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, hydroxy, amino, alkylamino, dialkylamino, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl,
  • Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted by one or more of halogen, nitro, cyano, Ci- 3 alkyl, Ci- 3 haloalkyl, phenyl, hydroxy, Ci ⁇ hydroxyalkyl, amino, Ci- 3 alkyl- or Ci- 3 dialkylamino, Ci- 3 alkoxy, Ci- 3 haloalkoxy, C 1-3 alkylthio, Ci- 3 haloalkylthio, Ci- 3 alkylsulfinyl, Ci ⁇ haloal
  • W is O, S or an oxetane group
  • R 2 and R 3 are independently H, halogen, Ci-C 3 alkyl or Ci-C 3 haloalkyl;
  • X 8 is a bond, -(CH 2 ) n where n is 1 to 3, -0-, -C(O)-, -S-, -S(O)-, -S(0) 2 -, -NHS(O)-, - S(0)-NH-, -NHS0 2 -, -S0 2 NH- or -NH-, wherein each CH 2 in -(CH 2 ) n - , -NHS(O)-, -S(O)- NH-, -NHS0 2 -, -S0 2 NH- or -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, hydroxy, amino, Ci- 3 alkylamino, Ci- 3 dialkylamino, Ci- 3 hydroxyalkyl, Ci- 3 aminoalkyl, Ci- 3 alkylamino-Ci-3_alkyl, Ci- 3 dialkylamino-Ci-3_alky
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L19 optionally substituted with halogen, Ci- 3 alkyl or Ci- 3 haloalkyl;
  • W is O
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-;
  • R 2 and R 3 are H; and n is 1 or 2.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloal
  • the ring is L20 optionally substituted with halogen, Ci- 3 alkyl or Ci- 3 haloalkyl;
  • W is O
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-;
  • R 2 and R 3 are H; and n is 1 or 2.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L21 optionally substituted with halogen, Ci- 3 alkyl or Ci- 3 haloalkyl;
  • W is O
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-;
  • R 2 and R 3 are H; and n is 1 or 2.
  • the ring is LI 9 optionally substituted with halogen, Ci- 3 alkyl or Ci- 3 haloalkyl;
  • W is O, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted with one or more halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfiny
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L19 optionally substituted with halogen, Ci- 3 alkyl or Ci- 3 haloalkyl;
  • W is O
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-;
  • R 2 and R 3 are H; and n is 1 or 2.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L20 optionally substituted with halogen, Ci- 3 alkyl or Ci- 3 haloalkyl;
  • W is O
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-;
  • R 2 and R 3 are H; and n is 1 or 2.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L21 optionally substituted with halogen, Ci- 3 alkyl or Ci- 3 haloalkyl;
  • W is O
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-;
  • R 2 and R 3 are H; and n is 1 or 2.
  • the ring is LI 9, L20 or L21, W is O, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted with one or more halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfony
  • the invention provides the compounds of formulae (IB- 1) and (IB-2) in Table 4 below, wherein Y, Xi, W, n, R 2 , R 3 , X 6 , X 8 , and the Ring (which includes variables Q 1 and Q2) are as described in the table.
  • Table 4 Compounds of formulae (IB- 1) and (IB-2). Compounds where Xi is a bond correspond to formula (IB- 1).
  • W and W are each O.
  • Xe is -NH- in which the hydrogen may be replaced by alkyl, haloalkyl or arylalkyl, -0-, -S-, -S(O)- or -S(0)2-.
  • X 6 is -(CH 2 ) n - optionally substituted by halogen, alkyl or haloalkyl.
  • the ring is LI 9, L20 or L21 optionally substituted with one to four substituents independently selected from halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl and haloalkynyl.
  • R2 and R3 are H.
  • n is 1 or 2.
  • R and R' is each independently hydrogen or alkyl.
  • Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted by one or more of halogen, nitro, cyano, SF 5 , Ci- 3 alkyl, Ci- 3 haloalkyl, phenyl, hydroxy, Ci- 3 hydroxyalkyl, amino, Ci- 3 alkyl- or Ci- 3 dialkylamino, Ci- 3 alkoxy, Ci- 3 haloalkoxy, Ci- 3 alkylthio, Ci- 3 haloalkylthio, Ci- 3 alkylsulfinyl,
  • W and W are independently O, S or an oxetane group
  • R and R' are independently H, Ci- 3 alkyl or Ci- 3 haloalkyl
  • R2 and R 3 are independently H, halogen, Ci-C 3 alkyl or Ci-C 3 haloalkyl;
  • X 6 is a bond, -(CH 2 ) n - where n is 1 to 3, -0-, -NH-, -C(0)-NH- and -NH-C(O)-, wherein each -CH 2 - in the -(CH 2 ) n - group, -NH-, -C(0)-NH- and -NH-C(O)- are optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, Ci ⁇ hydroxy alkyl, amino, Ci- 3 alkylamino, Ci- 3 dialkylamino, Ci- 3 aminoalkyl, Ci- 3 alkyl and Ci- 3 haloalkyl;
  • X 8 is absent or is a bond, -(CH 2 ) n where n is 1 to 3, -0-, -C(O)-, -S-, -S(O)-, -S(0) 2 -, - NHS(O)-, -S(0)-NH-, -NHS0 2 -, -S0 2 NH- or -NH-, wherein each CH 2 in -(CH 2 ) n - , - NHS(O)-, -S(0)-NH-, -NHS0 2 -, -S0 2 NH- or -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, hydroxy, amino, Ci-3alkylamino, Ci-3dialkylamino, Ci-3hydroxyalkyl, Ci-3aminoalkyl, Ci-3alkylamino-Ci-3- alkyl, Ci- 3 dialkylamino-Ci-3_alkyl, Ci- 3 al
  • W and W are O, Xe is -O- or -NH-, n is 1 or 2, R 2 and R 3 are H, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted with one or more halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkyl, haloalkylsul
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L19 optionally substituted with halogen, Ci_ 3 alkyl or Ci_ 3 haloalkyl;
  • W and W are O;
  • R and R' are H or Ci- 3 alkyl
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH- , wherein the -NH- is optionally substituted with a substituent selected from the group consisting of hydroxy-Ci- 3 -alkyl, Ci- 3 alkoxy-Ci- 3 _alkyl, amino-Ci- 3 _alkyl, Ci- 3 alkylamino-Ci- 3 _alkyl, Ci- 3 dialkylamino-Ci- 3 _alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl, C 2 -4alkenylcarbonyl, Ci- 3 alkyl, Ci- 3 haloalkyl, C 2 - 4 alkenyl, C 2 - 4 haloalkenyl, C 2 - 4 alkynyl, C 2 - 4 haloalkynyl, carbocyclyl, heterocyclyl, carbocyclyl
  • R 2 and R 3 are H; and n is 1 or 2.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L20 optionally substituted with halogen, Ci_ 3 alkyl or Ci_ 3 haloalkyl;
  • W and W are O;
  • R and R' are H or Ci- 3 alkyl
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH- , wherein the -NH- is optionally substituted with a substituent selected from the group consisting of hydroxy-Ci- 3 _alkyl, Ci- 3 alkoxy-Ci- 3 _alkyl, amino-Ci- 3 _alkyl, Ci- 3 alkylamino-Ci- 3 _alkyl, Ci- 3 dialkylamino-Ci- 3 _alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl, C 2 - 4 alkenylcarbonyl, Ci- 3 alkyl, Ci- 3 haloalkyl, C 2 - 4 alkenyl, C 2 - 4 haloalkenyl, C 2 - 4 alkynyl, C 2 - 4 haloalkynyl, carbocyclyl, heterocyclyl, carbocycly
  • R2 and R 3 are H; and n is 1 or 2.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L21 optionally substituted with halogen
  • W and W are O;
  • R and R' are H or Ci- 3 alkyl
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH- , wherein the -NH- is optionally substituted with a substituent selected from the group consisting of hydroxy-Ci-3-alkyl, Ci- 3 alkoxy-Ci-3_alkyl, amino-Ci-3-alkyl, Ci- 3 alkylamino-Ci-3_alkyl, Ci- 3 dialkylamino-Ci-3_alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl, C 2 -4alkenylcarbonyl, Ci- 3 alkyl, Ci- 3 haloalkyl, C 2 - 4 alkenyl, C 2 - 4 haloalkenyl, C 2 - 4 alkynyl, C 2 - 4 haloalkynyl, carbocyclyl, heterocyclyl, carbocyclyl-Ci- 3 alkyl and hetero
  • R 2 and R 3 are H; and n is 1 or 2.
  • the ring is LI 9, L20 or L21 optionally substituted with halogen, W and W are O, Y and/or Z are independently optionally substituted phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, wherein at least one of Y or Z is a bicyclic ring;
  • X 6 is -0-, n is 1 or 2, R 2 and R 3 are H; R and R' are H or Ci- 3 alkyl; and
  • X 8 is -NH-, - C(O)-, -CH 2 -, -CF 2 -, -CH(CH 3 )- or -C(CH 3 ) 2 -.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is LI 9, L20 or L21 optionally substituted with halogen, Ci_ 3 alkyl or Ci_ 3 haloalkyl;
  • W and W are O;
  • R and R' are H or Ci- 3 alkyl
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH- , wherein the -NH- is optionally substituted with a substituent selected from the group consisting of hydroxy-Ci- 3 _alkyl, alkoxy-Ci- 3 _alkyl, amino-Ci- 3 _alkyl, Ci- 3 alkylamino-Ci- 3 _alkyl, Ci- 3 dialkylamino-Ci- 3 _alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl, C 2 -4alkenylcarbonyl, Ci- 3 alkyl, Ci- 3 haloalkyl, C 2 - 4 alkenyl, C 2 - 4 haloalkenyl, C 2 - 4 alkynyl, C 2 - 4 haloalkynyl, carbocyclyl, heterocyclyl, carbocyclyl-Ci
  • R 2 and R 3 are H; and n is 1 or 2.
  • the ring is the ring is L19, L20 or L21 optionally substituted with halogen, Ci_ 3 alkyl or Ci_ 3 haloalkyl; W and W are O, Y and/or Z are independently optionally substituted phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, wherein at least one of Y or Z is a bicyclic ring; Xe is -0-, n is 1 or 2, R 2 and R 3 are H, and Xs is -NH-, -C(O)-, -CH 2 -, -CF 2 -, -CH(CH 3 )- or -C(CH 3 ) 2 -.
  • W and W are each O.
  • Xi is -0-, -S-, or -NH- in which the hydrogen atom may be replaced with alkyl, haloalkyl or arylalkyl.
  • Xs is -0-, -S-, or -NH- in which the hydrogen atom may be replaced with alkyl, haloalkyl or arylalkyl.
  • X is -NH- in which the hydrogen may be replaced by alkyl, haloalkyl or arylalkyl; -0-, -S-, - S(0)- or -S(0) 2 -.
  • X 6 is -(CH 2 ) n - optionally substituted by halogen, alkyl or haloalkyl.
  • ring is LI 9.
  • the ring is L20 or L21.
  • Xi is -(CH 2 ) n - optionally substituted by halogen, alkyl or haloalkyl.
  • R 2 and R 3 are H.
  • n is 1 or 2.
  • R and R' are independently hydrogen or alkyl.
  • W and W are O, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted with one or more halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloal
  • Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted by one or more of halogen, nitro, cyano, SF 5 , alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkyls
  • W and W are independently O, S or an oxetane group
  • the ring is LI 9, L20 or L21 optionally substituted with halogen, Ci_ 3 alkyl or Ci_ 3 haloalkyl;
  • R and R' are independently H, alkyl or haloalkyl
  • R 2 and R 3 are independently H, halogen, alkyl or haloalkyl
  • X 6 is a bond, -(CH 2 ) n - where n is 1 to 3, -0-, -NH-, -C(0)-NH- and -NH-C(O)-, wherein each -CH 2 - in the -(CH 2 ) n - group, -NH-, -C(0)-NH- and -NH-C(O)- is optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl and haloalkyl;
  • X 8 is a bond, -(CH 2 ) n where n is 1 to 3, -0-, -C(O)-, -S-, -S(O)-, -S(0) 2 -, -NHS(O)-, - S(0)-NH-, -NHSO2-, -SO2NH- or -
  • Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted by one or more of halogen, nitro, cyano, SF 5 , Ci- 3 alkyl, Ci- 3 haloalkyl, phenyl, hydroxy, Ci- 3 hydroxyalkyl, amino, Ci- 3 alkyl- or Ci-3dialkylamino, Ci-3alkoxy, Ci-3haloalkoxy, Ci-3alkylthio, Ci-3haloalkylthio, Ci- 3 alkylsulfinyl, Ci- 3 haloal
  • W and W are independently O, S or an oxetane group
  • the ring is LI 9, L20 or L21 optionally substituted with halogen, or Ci_ 3 haloalkyl;
  • R and R' are independently H, Ci-3alkyl or Ci-3haloalkyl
  • R2 and R3 are independently H, halogen, Ci-C 3 alkyl or Ci-C 3 haloalkyl;
  • X 6 is a bond, -(CH 2 ) n - where n is 1 to 3, -0-, -NH-, -C(0)-NH- and -NH-C(O)-, wherein each -CH 2 - in the -(CH 2 ) n - group, -NH-, -C(0)-NH- and -NH-C(O)- is optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, Ci ⁇ hydroxy alkyl, amino, Ci- 3 alkylamino, Ci- 3 dialkylamino, Ci- 3 aminoalkyl, Ci- 3 alkylamino-Ci-3-alkyl, Ci- 3 dialkylamino-Ci-3-alkyl, Ci- 3 alkyl and Ci- 3 haloalkyl;
  • X 8 is a bond, -(CH 2 ) n where n is 1 to 3, -0-, -C(0)-, -S-, -S(0)-, -S(0) 2 -, -NHS(O)-, -
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L19 optionally substituted with halogen, Ci- 3 alkyl or Ci- 3 haloalkyl;
  • W and W are O;
  • R and R' are H or Ci- 3 alkyl
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • X 8 is a bond, -C(O)-, -(CH 2 ) n - where n is 1 to 3, -0-CH 2 -, -NH-, -NHCH 2 -, -S-CH 2 -, -S(0)-CH 2 -, -CH 2 -S(0)-, -S(0) 2 -CH 2 -, and -CH 2 -S(0) 2 -, wherein each -(CH 2 ) n -, -0-CH 2 -, - NHCH 2 -, -S-CH 2 -, -S(0)-CH 2 -, -CH 2 -S(0)-, -S(0) 2 -CH 2 -, and -CH 2 -S(0) 2 -, wherein each -(CH 2 ) n -, -0-CH 2 -
  • R 2 and R3 are H; and n is 1 or 2.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L20 optionally substituted with halogen
  • W and W are O;
  • R and R' are H or Ci- 3 alkyl
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • R2 and R3 are H; and n is 1 or 2.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF5, and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L21 optionally substituted with halogen
  • W and W are O;
  • R and R' are H or Ci- 3 alkyl
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • R2 and R 3 are H; and n is 1 or 2.
  • the ring is LI 9 to L21, W and W are O, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted with one or more halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfon
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is LI 9;
  • W and W are O;
  • R and R' are H or Ci- 3 alkyl
  • Xi is a bond, -(CH 2 ) n - where n is 1 to 3, -NH-, wherein each -(CH 2 ) n - is optionally independently substituted with or one or more halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and the -NH- is optionally substituted with a substituent selected from the group consisting of hydroxy-Ci- 3 _alkyl, alkoxy-Ci-3-alkyl, amino-Ci-3-alkyl, Ci- 3 alkylamino-Ci-3_ alkyl, Ci- 3 dialkylamino-Ci-3_alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl, C 2 - 4alkenylcarbonyl, Ci- 3 alkyl, Ci- 3 haloalkyl, C 2 - 4 alkenyl, C 2 - 4 haloalkenyl, C 2
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, O, or -NH-, wherein each -(CH 2 ) n - is optionally independently substituted with or one or more halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and the -NH- is optionally substituted with a substituent selected from the group consisting of hydroxy-Ci-3_alkyl, alkoxy-Ci-3_alkyl, amino-Ci-3_alkyl, Ci- 3 alkylamino-Ci-3_alkyl, Ci- 3 dialkylamino-Ci-3_alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl, C2-4alkenylcarbonyl, Ci- 3 alkyl,
  • R2 and R3 are H; and n is 1 or 2.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L20;
  • W and W are O;
  • R and R' are H or Ci- 3 alkyl
  • Xi is a bond, -(CH 2 ) n - where n is 1 to 3, -NH-, wherein each -(CH 2 ) n - is optionally independently substituted with or one or more halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and the -NH- is optionally substituted with a substituent selected from the group consisting of hydroxy-Ci-3-alkyl, alkoxy-Ci-3-alkyl, amino-Ci-3-alkyl, Ci- 3 alkylamino-Ci-3_ alkyl, Ci- 3 dialkylamino-Ci-3_alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl, C2- 4 alkenylcarbonyl, Ci- 3 alkyl, Ci- 3 haloalkyl, C2- 4 alkenyl, C2- 4 haloalkenyl, C2- 4 alkynyl, C
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, O, or -NH-, wherein each -(CH 2 ) n - is optionally independently substituted with or one or more halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and the -NH- is optionally substituted with a substituent selected from the group consisting of hydroxy-Ci-3-alkyl, alkoxy-Ci-3-alkyl, amino-Ci-3-alkyl, Ci- 3 alkylamino-Ci-3-alkyl, Ci- 3 dialkylamino-Ci-3-alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl, C2-4alkenylcarbonyl, Ci- 3 alkyl, Ci- 3 haloalkyl, C2- 4 alkenyl, C2- 4 haloalkenyl, C2- 4 alkynyl
  • R2 and R 3 are H; and n is 1 or 2.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 or SF 5 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , SF 5 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • the ring is L21 ;
  • W and W are O;
  • R and R' are H or Ci- 3 alkyl
  • Xi is a bond, -(CH 2 ) n - where n is 1 to 3, -NH-, wherein each -(CH 2 ) n - is optionally independently substituted with or one or more halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and the -NH- is optionally substituted with a substituent selected from the group consisting of hydroxy-Ci-3-alkyl, alkoxy-Ci-3-alkyl, amino-Ci-3-alkyl, Ci- 3 alkylamino-Ci-3_ alkyl, Ci- 3 dialkylamino-Ci-3_alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl, C2- 4 alkenylcarbonyl, Ci- 3 alkyl, Ci- 3 haloalkyl, C2- 4 alkenyl, C2- 4 haloalkenyl, C2- 4 alkynyl, C
  • Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, O, or -NH-, wherein each -(CH 2 ) n - is optionally independently substituted with or one or more halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and the -NH- is optionally substituted with a substituent selected from the group consisting of hydroxy-Ci- 3 _alkyl, alkoxy-Ci-3-alkyl, amino-Ci-3-alkyl, Ci- 3 alkylamino-Ci-3_alkyl, Ci- 3 dialkylamino-Ci-3_alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl, C2- 4 alkenylcarbonyl, Ci- 3 alkyl, Ci- 3 haloalkyl, C2- 4 alkenylcarbonyl, Ci- 3 alkyl, Ci- 3 halo
  • R2 and R3 are H; and n is 1 or 2.
  • the ring is LI 9, L20 or L21, W and W are O, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted with one or more halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkyl
  • the invention provides the compounds of formulae (IB-3) and (IB-4) in Table 5 below, wherein Y, Xi, R, R', X 6 , Xs, Z and the Ring (includes variables Qi and Q 2 ) are described in the table and W, W are O, R 2 and R 3 are H, and n is 2:
  • the compounds of formula (I) have the structure (IC) shown below: ⁇ TM inkerTMz
  • Ring A is one of L19, L20 or L21 or a spirocyclic carbocyclic ring linker, a spirocyclic heterocyclic ring linker comprising two heterocyclic rings or a carbocyclic-heterocyclic ring system joined at one carbon, wherein each ring of the spirocyclic linker contains 4, 5 or 6 ring atoms, in which each of L19, L20, L21 or the spirocyclic ring linker is optionally independently substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl and haloalkynyl; and the Linker is the segment -X3-X4-X5-X6-X7-X8- where X3, X 4 , ⁇ 5 , ⁇ , X7 and Xs are as
  • Y and/or Z are naphthyl which is optionally substituted with one or more of halogen, nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroaryl
  • Y and/or Z are independently benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl each of which is optionally substituted with one or more of halogen, nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aryl,
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulf
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsul
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 , SCF 3 halothio, and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl.
  • the Ring A is LI 9. In another embodiment, the Ring A is L20 In still another embodiment, the Ring A is L21 as shown in Table 1 above. In another embodiment, Ring A is a spirocyclic carbocyclic ring linker, a spirocyclic heterocyclic ring linker comprising two heterocyclic rings or a carbocyclic -heterocyclic ring system joined at one carbon, wherein each ring of the spirocyclic linker contains 4, 5 or 6 ring atoms. In one embodiment of formula (IC), the compound has the structure (IC-1) shown below:
  • Ring A is LI 9, L20 or
  • W is O.
  • Ring A is L19 optionally substituted with halogen, Ci_ 3 alkyl or Ci_ 3 haloalkyl.
  • Ring A is L20 optionally substituted with halogen, Ci_ 3 alkyl or Ci_ 3 haloalkyl.
  • Ring A is L21 optionally substituted with halogen,
  • Y and/or Z is naphthyl which is optionally substituted with one or more halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
  • Y and/or Z are independently benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted with one or more halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl and
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl,
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 or SCF 3 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , S(0)Ci- 3 alkyl,
  • Xi is optionally substituted -(CH 2 ) n - or -C(O)-.
  • X 8 is -C(O)- or optionally substituted -NH- or -(CH 2 ) n -.
  • R 2 and R 3 are H.
  • n 1 or 2.
  • Xi is a bond, -C(O)- or -CH 2 -;
  • W is O, n is 1 or 2, and R 2 and R 3 are H.
  • Xi is a bond, -C(O)-, -(CH 2 ) n - where n is 1 to 3, -0-CH 2 -, -
  • the -NH- is optionally substituted with a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, where each substituent may be further independently substituted by hydroxy, hydroxy-Ci- 3 _alkyl, amino, Ci- 3 alkylamino, Ci- 3 dialkylamino or
  • Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted by one or more of halogen, nitro, cyano, Ci- 3 alkyl, Ci- 3 haloalkyl, phenyl, hydroxy, Ci- 3 hydroxyalkyl, amino, Ci- 3 alkyl- or Ci- 3(iialkylamino, Ci- 3 alkoxy, Ci- 3 haloalkoxy, C 1-3 alky lthio, Ci- 3 haloalkylthio, Ci- 3 alkylsulfinyl, Ci-
  • Ring A is LI 9 optionally substituted with halogen
  • W is O, S or an oxetane group
  • R 2 and R3 are independently H, halogen, Ci-C 3 alkyl or Ci-C 3 haloalkyl;
  • X 8 is is a bond, -(CH 2 ) n where n is 1 to 3, -0-, -C(O)-, -S-, -S(O)-, -S(0) 2 -, -NHS(O)-, -S(0)-NH-, -NHS0 2 -, -S0 2 NH- or -NH-, wherein each CH 2 in -(CH 2 ) n - , -NHS(O)-, -S(O)- NH-, -NHS0 2 -, -S0 2 NH- or -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, hydroxy, amino, Ci- 3 alkylamino, Ci- 3 dialkylamino, Ci- 3 hydroxyalkyl, Ci- 3 alkoxyalkyl, Ci- 3 aminoalkyl, Ci- 3 alkylamino-Ci-3_ alkyl, Ci- 3 dial
  • Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted by one or more of halogen, nitro, cyano, Ci- 3 alkyl, Ci- 3 haloalkyl, phenyl, hydroxy, Ci- 3 hydroxyalkyl, amino, Ci- 3 alkyl- or Ci- 3dialkylamino, Ci-3alkoxy, Ci-3haloalkoxy, C 1-3 alky lthio, Ci-3haloalky lthio, Ci- 3 alkylsulfinyl, Ci- 3 haloalkyl
  • Ring A is L20 optionally substituted with halogen
  • W is O, S or an oxetane group
  • R 2 and R3 are independently H, halogen, Ci-C 3 alkyl or Ci-C 3 haloalkyl;
  • X 8 is is a bond, -(CH 2 ) n where n is 1 to 3, -0-, -C(O)-, -S-, -S(O)-, -S(0) 2 -, -NHS(O)-, -S(0)-NH-, -NHS0 2 -, -S0 2 NH- or -NH-, wherein each CH 2 in -(CH 2 ) n - , -NHS(O)-, -S(O)- NH-, -NHS0 2 -, -S0 2 NH- or -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, hydroxy, amino, Ci-3alkylamino, Ci- 3 dialkylamino, Ci- 3 hydroxyalkyl, Ci- 3 alkoxyalkyl, Ci- 3 aminoalkyl, Ci- 3 alkylamino-Ci-3_ alkyl, Ci- 3 dialky
  • Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally substituted by one or more of halogen, nitro, cyano, Ci- 3 alkyl, Ci- 3 haloalkyl, phenyl, hydroxy, Ci- 3 hydroxyalkyl, amino, Ci- 3 alkyl- or Ci- 3dialkylamino, Ci-3alkoxy, Ci-3haloalkoxy, C 1-3 alky lthio, Ci-3haloalkylthio, Ci- 3 alkylsulfinyl, Ci- 3 haloalkyls
  • Ring A is L21 optionally substituted with halogen
  • W is O, S or an oxetane group
  • R 2 and R3 are independently H, halogen, Ci-C 3 alkyl or Ci-C 3 haloalkyl;
  • X 8 is is a bond, -(CH 2 ) n where n is 1 to 3, -0-, -C(O)-, -S-, -S(O)-, -S(0) 2 -, -NHS(O)-, -S(0)-NH-, -NHS0 2 -, -S0 2 NH- or -NH-, wherein each CH 2 in -(CH 2 ) n - , -NHS(O)-, -S(O)- NH-, -NHS0 2 -, -S0 2 NH- or -NH- is optionally independently substituted with one or two substituents selected from the group consisting of halogen, hydroxy, amino, Ci-3alkylamino, Ci- 3 dialkylamino, Ci- 3 hydroxyalkyl, Ci- 3 alkoxyalkyl, Ci- 3 aminoalkyl, Ci- 3 alkylamino-Ci-3_ alkyl, Ci- 3 dialky
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 or SCF 3 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • Ring A is LI 9 optionally substituted with halogen, Ci- 3 alkyl or Ci- 3 haloalkyl; W is O; Xe is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xi is a bond, -NH-, -(CH 2 ) n - where n is 1 to 3, or -C(O)-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-, where the -NH- is optionally substituted with a substituent selected from the group consisting of hydroxy-Ci-3_alkyl, alkoxy-Ci-3-alkyl, amino-Ci-3_alkyl, Ci- 3 alkylamino-Ci-3_alkyl, Ci- 3 dialkylamino-Ci-3_alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl, C2-4alkenylcarbonyl, Ci- 3 alkyl, Ci- 3 haloalkyl, C 2 - 4 alkenyl, C2- 4 haloalkenyl, C2- 4 alkynyl, C2- 4 haloalkynyl, carbocyclyl, heterocyclyl, carbocyclyl-Ci- 3 alkyl and heterocyclyl-Ci-3-alkyl, where
  • R2 and R 3 are H;
  • n 1 or 2.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 or SCF 3 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • Ring A is L20 optionally substituted with halogen
  • W is O;
  • X 6 is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xi is a bond, -NH-, -(CH 2 ) n - where n is 1 to 3, or -C(O)-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-, where the -NH- is optionally substituted with a substituent selected from the group consisting of hydroxy-Ci-3-alkyl, alkoxy-Ci-3-alkyl, amino-Ci-3-alkyl, Ci- 3 alkylamino-Ci-3_alkyl, Ci- 3 dialkylamino-Ci-3_alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl, C2- 4 alkenylcarbonyl, Ci- 3 alkyl, Ci- 3 haloalkyl, C 2 - 4 alkenyl, C2- 4 haloalkenyl, C2- 4 alkynyl, C2- 4 haloalkynyl, carbocyclyl, heterocyclyl, carbocyclyl-Ci- 3 alkyl and heterocyclyl-Ci-3_alkyl,
  • R2 and R 3 are H;
  • n 1 or 2.
  • one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted by one or more of chloro, fluoro, bromo, CF 3 , OCF 3 or SCF 3 , and the other of Y or Z is phenyl optionally substituted by cyano, nitro, CF 3 , S(0)Ci- 3 alkyl, S(0) 2 -Ci- 3 alkyl, S(0)Ci- 3 haloalkyl or S(0) 2 Ci- 3 haloalkyl;
  • W is O;
  • X 6 is a bond, -0-,-(CH 2 ) n - where n is 1 to 3 or -NH-;
  • Xs is a bond, -(CH 2 ) n - where n is 1 to 3, -O- or -NH-, where the -NH- is optionally substituted with a substituent selected from the group consisting of hydroxy-Ci- 3 _alkyl, alkoxy-Ci- 3 _alkyl, amino-Ci- 3 _alkyl, Ci- 3 alkylamino-Ci- 3 _alkyl, Ci- 3 dialkylamino-Ci- 3 _alkyl, Ci- 3 alkoxycarbonyl, Ci- 3 alkylcarbonyl, C 2 - 4 alkenylcarbonyl, Ci- 3 alkyl, Ci- 3 haloalkyl, C 2 - 4alkenyl, C 2 - 4 haloalkenyl, C 2 - 4 alkynyl, C 2 - 4 haloalkynyl, carbocyclyl, heterocyclyl, carbocyclyl-Ci-
  • R 2 and R 3 are H;
  • n 1 or 2.
  • Ring A is one of L19 to L21, Y and/or Z are independently naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, which is optionally substituted with one or more halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl;
  • Xi is bond, -C(O)- or -CH
  • the invention provides the compounds of formula (IC) in table 6 below:
  • the compounds of the invention were found to exhibit superior permeability compared with prior art compounds.
  • the permeability of a compound accross the epithelium cells along the gastrointestinal tract is an important limiting factor for the oral absorption and systemic availability of the compound.
  • the permeability of a systemically-acting compound is a feature that can significantly impact the efficacy of a compound against internal and/or external parasites when administered orally or topically.
  • the compounds of the invention exhibit surprisingly improved permeability compared with the compounds of the prior art having only monocyclic rings at the position corresponding to Y and/or Z (for example compounds of WO 2009/077527 and EP 2468096).
  • the significantly higher permeability of the compounds of the invention is expected to result in higher in vivo efficacy against internal parasites such as nematodes and external parasites that consume blood meals and/or reside in tissues such as the gastrointestinal mucosa. This is because the increased permeability accross the mammalian gut enhances the amount of the active compounds present in the blood circulation for delivery and uptake at the required sites.
  • the increased permeability of the compounds is likely to result in increased permeability accross the nematode cuticle/exo-membrane.
  • increased permeability of the active compounds may result in improved transdermal passage of the compounds into the bloodstream and/or tissues following topical administration.
  • the compounds of the invention exhibit about 20% to about 30% higher permeability than the prior art compounds. In another embodiment, the compounds of the invention exhibit about 40% to about 60% or about 50% to about 70% higher permeability than the prior art compounds. In still other embodiments, the compounds of the invention exhibit about 60% to about 100% higher permeability. In yet other embodiments, the compounds of the invention exhibit about 20% to about 50% or about 30% to about 75% higher permeability compared with the prior art compounds. In yet other embodiments, the compounds of the invention exhibit about 50% to about 100% higher permeability compared with the prior art compounds.
  • the compounds of the invention exhibit about 50% to about 500% greater permeability than the prior art compounds. In other embodiments, the compounds of the invention exhibit about 100% to about 500% greater permeability than the prior art compounds. In yet other embodiments, the compounds of the invention exhibit about 200% to about 400% greater permeability. In other embodiments, the compounds of the invention exhibit In yet other embodiments, the compounds of the invention exhibit about 100% to about 300% higher permeability or about 200% to about 300% greater permeability than the prior art compounds. In yet other embodiments, the compounds of the invention exhibit about 100% to about 200% higher permeability compared with the prior art compounds. In other embodiments, the compounds of the invention exhibit about 300% to about 500% higher permeability or about 400% to about 500% higher permeability compared with the prior art compounds.
  • the invention provides parasiticidal compositions which comprise at least one anthelmintic compound of formula (I) of the invention and a pharmaceutically acceptable carrier.
  • the composition of the invention can also be in a variety of forms which include, but are not limited to, oral formulations, injectable formulations, and topical, dermal or subdermal formulations.
  • the formulations are intended to be administered to an animal which includes but is not limited to mammals, birds and fish. Examples of mammals include but are not limited to humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats and other livestock or domestic mammals. Examples of birds include turkeys, chickens, ostriches and other livestock or domestic birds.
  • composition of the invention may be in a form suitable for oral use, for example, as baits (see, e.g., U.S. Patent No. 4,564,631, incorporated herein by reference), dietary supplements, troches, lozenges, chewables, tablets, hard or soft capsules, emulsions, aqueous or oily suspensions, aqueous or oily solutions, oral drench formulations, dispersible powders or granules, premixes, syrups or elixirs, enteric formulations or pastes.
  • compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, bittering agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc, the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents for example, corn starch, or alginic acid
  • binding agents for example starch,
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in U.S. Patent Nos. 4,256, 108; 4, 166,452; and 4,265,874 (incorporated herein by reference) to form osmotic therapeutic tablets for controlled release.
  • Formulations for oral use may be hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin.
  • Capsules may also be soft gelatin capsules, wherein the active ingredient is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • compositions of the invention may also be in the form of oil-in- water or water-in- oil emulsions.
  • the oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example, soybean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening agents, bittering agents, flavoring agents, and/or preservatives.
  • the composition of the invention is in the form of a microemulsion.
  • Microemulsions are well suited as the liquid carrier vehicle. Microemulsions are quaternary systems comprising an aqueous phase, an oily phase, a surfactant and a co-surfactant. They are translucent and isotropic liquids.
  • Microemulsions are composed of stable dispersions of microdroplets of the aqueous phase in the oily phase or conversely of microdroplets of the oily phase in the aqueous phase.
  • the size of these microdroplets is less than 200 nm (1000 to 100,000 nm for emulsions).
  • the interfacial film is composed of an alternation of surface-active (SA) and co-surface-active (Co-SA) molecules which, by lowering the interfacial tension, allows the microemulsion to be formed spontaneously.
  • the oily phase can be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or alternatively from mixtures of such compounds.
  • the oily phase comprises of triglycerides; in another embodiment of the oily phase, the triglycerides are medium-chain triglycerides, for example Cs-Cio caprylic/capric triglyceride.
  • the oily phase will represent a % v/v range selected from the group consisting of about 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v/v of the microemulsion.
  • the aqueous phase includes, for example water or glycol derivatives, such as propylene glycol, glycol ethers, polyethylene glycols or glycerol.
  • glycol derivatives such as propylene glycol, glycol ethers, polyethylene glycols or glycerol.
  • the glycol is selected from the group consisting of propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether and mixtures thereof.
  • the aqueous phase will represent a proportion from about 1 to about 4% v/v in the microemulsion.
  • Surfactants for the microemulsion include diethylene glycol monoethyl ether, dipropyelene glycol monomethyl ether, polyglycolized Cs-Cio glycerides or polyglyceryl-6 dioleate.
  • the co-surfactants include short-chain alcohols, such as ethanol and propanol.
  • the co-surfactant to surfactant ratio will be from about 1/7 to about 1/2. In another embodiment for the amount of co-surfactant, there will be from about 25 to about 75% v/v of surfactant and from about 10 to about 55% v/v of co-surfactant in the microemulsion.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as sucrose, saccharin or aspartame, bittering agents, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid, or other known preservatives.
  • Aqueous suspensions may contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide, with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorb
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents and/or bittering agents, such as those set forth above.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents and/or bittering agents, such as those set forth above.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, bittering, flavoring and coloring agents, may also be present.
  • Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring agent(s) and/or coloring agent(s).
  • the process for preparing a paste formulation comprises the steps of:
  • step (c) allowing the intermediate formed in (b) to settle for a time sufficient in order to allow the air entrapped during step (b) to escape;
  • step (a) can be the last step.
  • the formulation is a paste containing at least one anthelmintic compound of formula (I), fumed silica, a viscosity modifier, an absorbent, a colorant; and a hydrophilic carrier which is triacetin, a monoglyceride, a diglyceride, or a triglyceride.
  • the paste may also include, but is not limited to, a viscosity modifier selected from the group consisting of PEG 200, PEG 300, PEG 400, PEG 600, monoethanolamine, triethanolamine, glycerol, propylene glycol, polyoxyethylene (20) sorbitan mono-oleate (POLYSORBATE 80 or TWEEN 80), and poloxomers (e.g., PLURONIC L 81); an absorbent selected from the group consisting of magnesium carbonate, calcium carbonate, starch, and cellulose and its derivatives; and a colorant selected from the group consisting of titanium dioxide iron oxide, and FD&C Blue #1 ALUMINUM LAKE.
  • a viscosity modifier selected from the group consisting of PEG 200, PEG 300, PEG 400, PEG 600, monoethanolamine, triethanolamine, glycerol, propylene glycol, polyoxyethylene (20) sorbitan mono-oleate (POLYSORBATE 80 or TWEEN 80), and poloxomers (e
  • compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • Co-solvents such as ethanol, propylene glycol glycerol formal or polyethylene glycols may also be used.
  • Preservatives such as phenol or benzyl alcohol, may be used.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectable compositions.
  • Topical, dermal and subdermal formulations can include emulsions, creams, ointments, gels, pastes, powders, shampoos, pour-on formulations, ready-to-use formulations, spot-on solutions and suspensions, dips and sprays.
  • Topical application of an inventive compound or of a composition including at least one inventive compound among active agent(s) therein, a spot-on or pour-on composition can allow for the inventive compound to be absorbed through the skin to achieve systemic levels, distributed through the sebaceous glands or on the surface of the skin achieving levels throughout the hair coat. When the compound is distributed through the sebaceous glands, they can act as a reservoir, whereby there can be a long-lasting effect (up to several months) effect.
  • Spot-on formulations are typically applied in a localized region which refers to an area other than the entire animal.
  • a localized region the location is between the shoulders.
  • a localized region it is a stripe, e.g. a stripe from head to tail of the animal.
  • pour-on formulations are described in U.S. Patent No. 6,010,710, incorporated herein by reference.
  • the pour-on formulations may be advantageously oily, and generally comprise a diluent or vehicle and also a solvent (e.g. an organic solvent) for the active ingredient if the latter is not soluble in the diluent.
  • a solvent e.g. an organic solvent
  • Organic solvents that can be used in the invention include but are not limited to: acetyltributyl citrate, fatty acid esters such as the dimethyl ester, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone including N-methylpyrrolidone, diethylene glycol monoethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, ethylene glycol, diisobutyl adipate, diisopropyl adipate (also known as CERAPHYL 230), triacetin, buty
  • the pharmaceutically or veterinarily acceptable carrier of the formulation comprises Ci-Cio alcohols or esters thereof (including acetates, such as ethyl acetate, butyl acetate and the like), Cio-Cis saturated fatty acids or esters thereof, Cio-Cis monounsaturated fatty acids or esters thereof, monoesters or diesters of aliphatic diacids, glycerol monoesters (e.g. monoglycerides), glycerol diesters (e.g. diglycerides), glycerol triesters (e.g.
  • triglycerides such as triacetin
  • glycols such as triacetin
  • glycol ethers such as glycol esters or glycol carbonates
  • PEGs polyethylene glycols of various grades
  • monoethers such as diethers, monoesters or diesters thereof (e.g. diethylene glycol monoethyl ether), or mixtures thereof.
  • plant oils such as, but not limited to soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, coconut oils etc.
  • mineral oils such as, but not limited to, petrolatum, paraffin, silicone, etc.
  • an emollient and/or spreading and/or film-forming agent can be added.
  • One embodiment of the emollient and/or spreading and/or film-forming agent are those agents selected from the group consisting of:
  • polyvinylpyrrolidone polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, 2-pyrrolidones including, but not limited to N-methylpyrrolidone, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oils, polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS) oils), for example those containing silanol functionalities, or a 45V2 oil,
  • PDMS polydimethylsiloxane
  • anionic surfactants such as alkaline stearates, sodium, potassium or ammonium stearates; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulfates (e.g. sodium lauryl sulfate and sodium cetyl sulfate); sodium dodecylbenzenesulfonate, sodium dioctylsulfosuccinate; fatty acids (e.g. those derived from coconut oil),
  • cationic surfactants such as water-soluble quaternary ammonium salts of formula N R'R"R"'R"", Y " in which the radicals R are optionally hydroxylated hydrocarbon radicals and Y " is an anion of a strong acid such as the halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is among the cationic surfactants which can be used,
  • nonionic surfactants such as sorbitan esters, which are optionally polyoxyethylenated (e.g. POLYSORBATE 80), polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrol ether; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide,
  • nonionic surfactants such as sorbitan esters, which are optionally polyoxyethylenated (e.g. POLYSORBATE 80), polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrol ether; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil
  • amphoteric surfactants such as the substituted lauryl compounds of betaine; or (g) a mixture of at least two of these agents.
  • the solvent will be used in proportion with the concentration of the anthelmintic compound of formula (I) and its solubility in this solvent. It will be sought to have the lowest possible volume. The vehicle makes up the difference to 100%.
  • the emollient is used in a proportion of from 0.1 to 50% and 0.25 to 5%, by volume.
  • the composition in ready-to-use solution form as is described in U.S. Patent No. 6,395,765, incorporated herein by reference.
  • the ready-to-use solution can contain a crystallization inhibitor, an organic solvent and an organic co-solvent.
  • the crystallization inhibitor can be present in a proportion of about 1 to about 30% (w/v) in the composition. In other embodiments, the crystallization inhibitor may be present in a proportion of about 1 to about 20% (w/v) and about 5 to about 15%. Acceptable inhibitors are those whose addition to the formulation inhibits the formation of crystals when the formulation is applied. In some embodiments, formulations may include compounds that function as crystallization inhibitors other than those listed herein.
  • the suitability of a crystallization inhibitor may be determined by a the test in which 0.3 ml of a solution comprising 10% (w/v) of an anthelmintic compound of the invention in the liquid carrier and 10% of the inhibitor are deposited on a glass slide at 20°C and allowed to stand for 24 hours. The slide is then observed with the naked eye. Acceptable inhibitors are those whose addition provides for few (e.g. less than ten crystals) or no crystal.
  • the organic solvent has a dielectric constant of a range selected from the group consisting of between about 2 to about 35, about 10 to about 35 or about 20 to about 30. In other embodiments, the solvent will have a dielectric constant of between about 2 and about 20, or between about 2 and about 10.
  • the content of this organic solvent in the overall composition represents the complement to 100% of the composition.
  • the solvent may comprise a mixture of solvents including a mixture of an organic solvent and an organic co-solvent.
  • the organic co-solvent has a boiling point of less than about 300° C or less than about 250° C. In other embodiments, the co-solvent has a boiling point of below about 200° C, or below about 130° C. In still another embodiment of the invention, the organic co-solvent has a boiling point of below about 100° C, or below about 80° C. In still other embodiments, the organic co-solvent will have a dielectric constant of a range selected from the group consisting of about 2 to about 40, about 10 to about 40, or typically about 20 to about 30.
  • this co-solvent may be present in the composition in an organic co- solvent/organic solvent weight/weight (W/W) ratio of about 1/15 to about 1/2.
  • the co-solvent is volatile so as to act as a drying promoter, and is miscible with water and/or with the organic solvent.
  • the formulation can also comprise an antioxidizing agent intended to inhibit oxidation in air, this agent being present in a proportion selected from a range consisting of about 0.005 to about 1% (w/v) and about 0.01 to about 0.05%.
  • Crystallization inhibitors which are useful for the invention include but are not limited to:
  • polyvinylpyrrolidone polyvinyl alcohols, copolymers of vinyl acetate and of vinylpyrrolidone, polyethylene glycols of various grades, benzyl alcohol, 2-pyrrolidones including, but not limited to N-methylpyrrolidone, dimethylsulfoxide, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; a solvent as described herein that is capable of inhibiting crystal formation; acrylic derivatives, such as acrylates and methacrylates or other polymers derived from acrylic monomers, and others;
  • anionic surfactants such as alkaline stearates (e.g. sodium, potassium or ammonium stearate); calcium stearate or triethanolamine stearate; sodium abietate; alkyl sulfates, which include but are not limited to sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctyl sulfosuccinate; or fatty acids (e.g. coconut oil);
  • alkaline stearates e.g. sodium, potassium or ammonium stearate
  • calcium stearate or triethanolamine stearate e.g. calcium stearate or triethanolamine stearate
  • sodium abietate e.g. sodium stearate
  • alkyl sulfates which include but are not limited to sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenes
  • cationic surfactants such as water-soluble quaternary ammonium salts of formula N R'R"R'"R""Y ⁇ , in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals and Y is an anion of a strong acid, such as halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is one of the cationic surfactants which can be used;
  • non-ionic surfactants such as optionally polyoxyethylenated esters of sorbitan, e.g. POLYSORBATE 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and of propylene oxide;
  • non-ionic surfactants such as optionally polyoxyethylenated esters of sorbitan, e.g. POLYSORBATE 80, or polyoxyethylenated alkyl ethers
  • polyethylene glycol stearate polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and of propylene
  • amphoteric surfactants such as substituted lauryl compounds of betaine
  • a crystallization inhibitor pair will be used.
  • Such pairs include, for example, the combination of a film- forming agent of polymeric type and of a surface-active agent. These agents will be selected from the compounds mentioned above as crystallization inhibitor.
  • the agents are of the polymeric type which include but are not limited to the various grades of polyvinylpyrrolidone, polyvinyl alcohols, and copolymers of vinyl acetate and of vinylpyrrolidone.
  • the agents include but are not limited to those made of non-ionic surfactants; in another embodiment of the surface active agents, the agent is a polyoxyethylenated esters of sorbitan and in yet another embodiment of the surface-active agent, the agents include the various grades of POLYSORBATE, for example POLYSORBATE 80.
  • the film- forming agent and the surface-active agent can be incorporated in similar or identical amounts within the limit of the total amounts of crystallization inhibitor mentioned elsewhere.
  • the pair thus constituted secures, in a noteworthy way, the objectives of absence of crystallization on the coat and of maintenance of the cosmetic appearance of the skin or fur, that is to say without a tendency towards sticking or towards a sticky appearance, despite the high concentration of active material.
  • the agents are those conventional in the art and include but is not limited to butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium metabisulphite, propyl gallate, sodium thiosulfate or a mixture of not more than two of them.
  • composition adjuvants discussed above are well known to the practitioner in this art and may be obtained commercially or through known techniques. These concentrated compositions are generally prepared by simple mixing of the constituents as defined above; advantageously, the starting point is to mix the active material in the main solvent and then the other ingredients or adjuvants are added.
  • the volume applied is not restricted as long as the amount of substance administered is shown to be safe and efficacious. Typically, the volume applied depends on the size and weight of the animal as well as the concentration of active, the extent of infestation by parasites and the type of administration. In some embodiments, the volume applied can be of the order of about 0.3 to about 5 ml or about 0.3 ml to about 1 ml. In one embodiment for the volume, the volume is on the order of about 0.5 ml, for cats and on the order of about 0.3 to about 3 ml for dogs, depending on the weight of the animal.
  • application of a spot-on formulation according to the present invention can also provide long-lasting and broad-spectrum efficacy when the solution is applied to the mammal or bird.
  • the spot-on formulations provide for topical administration of a concentrated solution, suspension, microemulsion or emulsion for intermittent application to a spot on the animal, generally between the two shoulders (solution of spot-on type).
  • the carrier can be a liquid carrier vehicle as described in U.S. Patent No. 6,426,333 (incorporated herein by reference), which in one embodiment of the spot-on formulation comprises a solvent and a co-solvent wherein the solvent is selected from the group consisting of acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, diisobutyl adipate, diisopropyl adipate (also known as CERAPHYL 230), triacetin, butyl acetate, octyl acetate, propylene carbonate, butylene carbonate, dimethylsulfoxide, organic amides including dimethylformamide and dimethylacetamide, ethanol, isopropanol, methanol, ethylene glycol monoethy
  • the pharmaceutically or veterinarily acceptable carrier of the formulation comprises Ci-Cio alcohols or esters thereof (including acetates, such as ethyl acetate, butyl acetate and the like), Cio-Cis saturated fatty acids or esters thereof, Cio-Cis monounsaturated fatty acids or esters thereof, monoesters or diesters of aliphatic diacids, glycerol monoesters (e.g. monoglycerides), glycerol diesters (e.g. diglycerides), glycerol triesters (e.g.
  • triglycerides such as triacetin
  • glycols such as triacetin
  • glycol ethers such as glycol esters or glycol carbonates
  • PEGs polyethylene glycols of various grades
  • monoethers such as diethers, monoesters or diesters thereof (e.g. diethylene glycol monoethyl ether), or mixtures thereof.
  • the liquid carrier vehicle can optionally contain a crystallization inhibitor including an anionic surfactant, a cationic surfactant, a non-ionic surfactant, an amine salt, an amphoteric surfactant or polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, 2-pyrrolidone including N-methylpyrrolidone (NMP), dimethylsulfoxide, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, solvents as defined herein that can inhibit the formation of crystals, and acrylic derivatives such acrylates or methacrylates as well as other polymers derived from acrylic monomers, or a mixture of these crystallization inhibitors.
  • a crystallization inhibitor including an anionic surfactant, a cationic surfactant, a non-i
  • Spot-on formulations may be prepared by dissolving the active ingredients into the pharmaceutically or veterinary acceptable vehicle.
  • the spot-on formulation can be prepared by encapsulation of the active ingredient to leave a residue of the therapeutic agent on the surface of the animal.
  • These formulations will vary with regard to the weight of the therapeutic agent in the combination depending on the species of host animal to be treated, the severity and type of infection and the body weight of the host.
  • Dosage forms may contain from about 0.5 mg to about 5 g of an active agent.
  • the dosage is from about 1 mg to about 500 mg of an active agent, typically about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, or about 1000 mg.
  • the active agent is present in the formulation at a concentration of about 0.05% to about 50% weight/volume. In other embodiments, the active agent may be present in the formulation at a concentration of about 0.1% to about 30%, about 0.5% to about 20% (w/v) or about 1% to about 10% (w/v). In another embodiment of the invention, the active agent is present in the formulation as a concentration from about 0.1 to 2% weight/volume. In yet another embodiment of the invention, the active agent is present in the formulation as a concentration from about 0.25 to about 1.5% weight/volume. In still another embodiment of the invention, the active agent is present in the formulation as a concentration about 1% weight/volume.
  • the dose of the inventive compounds is about 0.1 mg/kg to about 100 mg/kg.
  • the dose of the inventive compounds is about 0.5 mg/kg to about 70 mg/kg, about 0.5 mg/kg to about 50 mg/kg or about 0.5 mg/kg to about 30 mg/kg.
  • the dose is 0.5 mg/kg to about 30 mg/kg, 0.5 mg/kg to about 20 mg/kg or 0.5 mg/kg to about 10 mg/kg. More typically, in some embodiments the dose of the active compounds is about 0.1 mg/kg to 5 mg/kg, 0.1 mg/kg to about 3 mg/kg, or about 0.1 mg/kg to 1.5 mg/kg.
  • the dose may be as low as 0.1 mg/kg (0.02 mg/ml), about 0.2 mg/kg (0.04 mg/ml), about 0.3 mg/kg (0.06 mg/ml), about 0.4 mg/kg (0.08 mg/ml), about 0.5 mg/kg (0.1 mg/ml), about 0.6 mg/kg (0.12 mg/ml), about 0.7 mg/kg (0.14 mg/ml), about 0.8 mg/kg (0.16 mg/ml), about 0.9 mg/kg (0.18 mg/ml), about 1.0 mg/kg (0.2 mg/ml).
  • Another embodiment of the invention is directed toward a method of treating endoparasitic infestation or infection in an animal, comprising administering an effective amount of the compound of the invention to the animal in need thereof.
  • the compounds of the invention have been shown to have superior efficacy against endoparasites, and in particular against parasites that are resistant to active agents of the macrocyclic lactone class.
  • a compound of the invention has been shown to have superior efficacy against ivermectin-resistant endoparasites in sheep.
  • Figure 2 shows that a compound of the invention (compound 3.024) administered at a dosage of 1.5 mg/kg or 3 mg/kg orally had greater than 95% efficacy against ivermectin-resistant strains of Haemonchus contortus, Ostertagia circumcincta and Trichostrongylus columbriformis.
  • ivermectin administered orally at a dose of 0.2 mg/kg was almost completely inactive against Haemonchus contortus, less than 30% effective against Ostertagia circumcincta and less than 60% effective against Trichostrongylus columbriformis. It is surprising that the compounds of the invention have superior efficacy against endoparasites that are resistant to ivermectin, which is one of the most potent active agents known against endo- and ectoparasites.
  • the invention provides a method for treating an endoparasitic infestation or infection in an animal, comprising administering an effective amount of an anthelmintic compound of the invention in combination with an effective amount of activators of invertebrate GABA receptors including an avermectin or milbemycin to the animal in need thereof.
  • Avermectins that may be used in combination with the compounds of the invention include, but are not limited to abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, and selamectin
  • Milbemycins compounds that may be used in combination with the compounds of the invention include, but are not limited to, milbemectin, milbemycin D, moxidectin and nemadectin. Also included are the 5-oxo and 5-oxime derivatives of said avermectins and milbemycins.
  • the compounds and compositions of the invention may be used for treating endoparasiticidal infection or infestation an endoparasite including, but not limited to, Anaplocephala (Anoplocephala) , Ancylostoma, Anecator, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Cyathostomum, Cylicocyclus, Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofllaria, Dracunculus, Echinococcus, Enterobius, Fasciola, Filaroides, Habronema, Haemonchus, Metastrongylus, Moniezia, Necator, Nematodirus, Nippostrongylus, Oesophagostumum, Onchocerca, Ostertagia, Oxyuris, Parascaris, Schistosoma
  • the compounds and compositions of the invention are used to treat or prevent an infection by Dirofllaria immitis. In another embodiment the compounds and compositions of the invention are used to treat or prevent an infection by Dirofllaria repens.
  • the helminth is Haemonchus contortus, Ostertagia circumcincta, Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia curticei, Nematodirus battus and combinations thereof.
  • Another embodiment of the invention is directed toward a method of treating ectoparasitic infestation or infection in an animal in need thereof which comprises administering an effective amount of the compound of the invention to the animal in need thereof.
  • the infection or infestation is caused by fleas, ticks, mites, mosquitoes, flies, lice, blowfly and combinations thereof.
  • invention provides a method for treating an ectoparasitic infestation or infection in an animal, comprising administering an effective amount of an anthelmintic compound of the invention in combination with an effective amount of an avermectin or milbemycin active agent to the animal in need thereof.
  • the compounds of the invention may be used to protect plants and crops. In other embodiments, the compounds may be used to treat environmental surfaces and structures.
  • the compounds of formula (I) or their salts can be employed as such or in the form of their preparations (formulations) as combinations with other active substances, such as, for example, insecticides, attractants, sterilants, acaricides, nematicides, and with growth regulators.
  • active substances such as, for example, insecticides, attractants, sterilants, acaricides, nematicides, and with growth regulators.
  • Bactericides include, but are not limited to, bronopol, dichlorophen, nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octhilinone, furancarboxylic acid, oxytetracycline, probenazole, streptomycin, tecloftalam, copper sulphate and other copper preparations.
  • Insecticides/acaricides/nematicides include those compounds mentioned in U.S. Patent Nos. 7,420,062 and 7,001,903, U.S. Patent publication 2008/0234331, each incorporated herein by reference, the literature known to the person skilled in the art, and the compounds classified by IRAC (Insecticide Resistance Action Committee).
  • insecticides/acaricides/nematicides include, but are limited to, carbamates; triazemate; organophosphates; cyclodiene organochlorines; phenylpyrazoles; DDT; methoxychlor; pyrethroids; pyrethrins; neonicotinoids; nicotine; bensultap; cartap hydrochloride; nereistoxin analogues; spinosyns; avermectins and milbemycins; juvenile hormone analogues; fenoxycarb; fenoxycarb; alkyl halides; chloropicrin; sulfuryl fluoride; cryolite; pymetrozine; flonicamid; clofentezine; hexythiazox; etoxazole; Bacillus sphaericus; diafenthiuron; organotin miticides; propargite; tetradifon; chlorfenapyr;
  • the compounds of formula (I) can be formulated in various ways, depending on the prevailing biological and/or chemico-physical parameters.
  • examples of possible formulations which are suitable are: wettable powders (WP), water-soluble powders (SP), water-soluble concentrates, emulsifiable concentrates (EC), emulsions (EW) such as oil-in- water and water-in-oil emulsions, sprayable solutions, suspension concentrates (SC), dispersions on an oil or water basis, solutions which are miscible with oil, capsule suspensions (CS), dusts (DP), seed-dressing products, granules for broadcasting and soil application, granules (GR) in the form of microgranules, spray granules, coated granules and adsorption granules, water-dispersible granules (WG), water-soluble granules (SG), ULV formulations, microcapsules and waxes.
  • WP wettable powders
  • Solid state forms of the compounds of formula (I) can be prepared by methods known in the art, e.g. Byrn et al, “Solid-State Chemistry of Drugs", 2 nd Edition, SSCI Inc., (1999); Glusker et al, “Crystal Structure Analysis - A Primer", 2 nd Edition, Oxford University Press, (1985).
  • the formulations mentioned can be prepared in a manner known per se, for example by mixing the active compounds with at least one solvent or diluent, emulsifier, dispersant and/or binder or fixative, water repellent and optionally one or more of a desiccant, UV stabilizer, a colorant, a pigment and other processing auxiliaries.
  • Wettable powders are preparations which are uniformly dispersible in water and which, besides the compounds of formula (I), also comprise ionic and/or nonionic surfactants (wetters, dispersants), for example, polyoxyethylated alkylphenols, polyoxyethylated fatty alcohols, polyoxyethylated fatty amines, fatty alcohol polyglycol ether sulfates, alkanesulfonates or alkylbenzenesulfonates, sodium lignosulfonate, sodium 2,2'-dinaphthylmethane-6,6'-disulfonate, sodium dibutylnaphthalenesulfonate or else sodium oleoylmethyltaurinate, in addition to a diluent or inert substance.
  • ionic and/or nonionic surfactants for example, polyoxyethylated alkylphenols, polyoxyethylated fatty alcohols, polyoxye
  • the compounds of formula (I) are, for example, ground finely in conventional apparatuses such as hammer mills, blower mills and air-jet mills and mixed with the formulation auxiliaries, either concomitantly or thereafter.
  • Emulsifiable concentrates are prepared, for example, by dissolving the compounds of formula (I) in an organic solvent, for example butanol, cyclohexanone, dimethylformamide, xylene or else higher-boiling aromatics or hydrocarbons or mixtures of these, with addition of one or more ionic and/or nonionic surfactants (emulsifiers).
  • organic solvent for example butanol, cyclohexanone, dimethylformamide, xylene or else higher-boiling aromatics or hydrocarbons or mixtures of these.
  • Emulsifiers which can be used are, for example: calcium salts of alkylarylsulfonic acids, such as calcium dodecylbenzenesulfonate or nonionic emulsifiers, such as fatty acid polyglycol esters, alkylaryl polyglycol ethers, fatty alcohol polyglycol ethers, propylene oxide/ethylene oxide condensates, alkyl polyethers, sorbitan esters such as sorbitan fatty acid esters or polyoxyethylene sorbitan esters such as polyoxyethylene sorbitan fatty acid esters.
  • alkylarylsulfonic acids such as calcium dodecylbenzenesulfonate or nonionic emulsifiers
  • fatty acid polyglycol esters alkylaryl polyglycol ethers, fatty alcohol polyglycol ethers, propylene oxide/ethylene oxide condensates
  • alkyl polyethers sorbitan esters such as sorbitan
  • Dusts are obtained by grinding the active substance with finely divided solid substances, for example talc or natural clays, such as kaolin, bentonite or pyrophyllite, or diatomaceous earth.
  • finely divided solid substances for example talc or natural clays, such as kaolin, bentonite or pyrophyllite, or diatomaceous earth.
  • Suspension concentrates may be water- or oil-based. They can be prepared, for example, by wet grinding by means of commercially available bead mills, if appropriate with addition of surfactants, as they have already been mentioned above for example in the case of the other formulation types.
  • Emulsions for example oil-in-water emulsions (EW)
  • EW oil-in-water emulsions
  • Granules can be prepared either by spraying the compounds of formula (I) onto adsorptive, granulated inert material or by applying active substance concentrates onto the surface of carriers such as sand, kaolinites or of granulated inert material, by means of binders, for example polyvinyl alcohol, sodium polyacrylate or alternatively mineral oils. Suitable active substances can also be granulated in the manner which is conventional for the production of fertilizer granules, if desired in a mixture with fertilizers.
  • Water-dispersible granules are prepared, as a rule, by the customary processes such as spray-drying, fluidized-bed granulation, disk granulation, mixing in high-speed mixers and extrusion without solid inert material.
  • To prepare disk, fluidized-bed, extruder and spray granules see, for example, processes in "Spray-Drying Handbook” 3rd ed. 1979, G. Goodwin Ltd., London; J.E. Browning, "Agglomeration”, Chemical and Engineering 1967, pages 147 et seq.; "Perry's Chemical Engineer's Handbook", 5th Ed., McGraw-Hill, New York 1973, p. 8-57.
  • the agrochemical preparations comprise a range selected from the group consisting of about 0.1 to about 99% by weight and about 0.1 to about 95% by weight, of compounds of formula (I).
  • the concentration of compounds of formula (I) in wettable powders is, for example, about 10 to about 90% by weight, the remainder to 100% by weight being composed of customary formulation components.
  • the concentration of compounds of formula (I) can amount to ranges selected from the group consisting of about 1% to about 90% and about 5% to about 80% by weight.
  • Formulations in the form of dusts usually comprise in the range selected from the group consisting of about 1% to about 30% by weight of compounds of formula (I) and about 5% to about 20% by weight of compounds of formula (I).
  • For sprayable solutions comprise a range selected from the group consisting of about 0.05% to about 80% by weight of compounds of formula (I) and about 2% to about 50% by weight of compounds of formula (I).
  • the content of compounds of formula (I) depends partly on whether the compounds of formula (I) are in liquid or solid form and on which granulation auxiliaries, fillers and the like are being used.
  • the water-dispersible granules for example, comprise a range selected from the group consisting of between about 1 and about 95% and between about 10% and about 80% by weight.
  • formulations of compounds of formula (I) mentioned comprise, if appropriate, the adhesives, wetters, dispersants, emulsifiers, penetrants, preservatives, antifreeze agents, solvents, fillers, carriers, colorants, antifoams, evaporation inhibitors, pH regulators and viscosity regulators which are conventional in each case.
  • Additional pharmaceutically or veterinarily active ingredients may also be added to the compositions of the invention.
  • the additional active agents may be one or more parasiticidal compounds including acaricides, anthelmintics, endectocides and insecticides.
  • Anti-parasitic agents can include both ectoparasiticisal and endoparasiticidal agents.
  • compositions of the invention with the inventive anthelmintic compounds are well-known in the art (see e.g. Plumb ' Veterinary Drug Handbook, 5 th Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9 th Edition, (January 2005)) and include but are not limited to acarbose, acepromazine maleate, acetaminophen, acetazolamide, acetazolamide sodium, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentamide hydrogen sulfate, aminophylline/theophylline, amiodarone
  • arylpyrazole compounds such as phenylpyrazoles, known in the art may be combined with the anthelmintic compounds of the invention.
  • arylpyrazole compounds include but are not limited to those described in U.S. Patent Nos. 6,001,384; 6,010,710; 6,083,519; 6,096,329; 6, 174,540; 6,685,954 and 6,998, 131 (all of which are incorporated herein by reference, each assigned to Merial, Ltd., Duluth, GA).
  • On particularly preferred arylpyrazole compound is fipronil.
  • one or more macrocyclic lactones or lactams which act as an acaricide, anthelmintic agent and/or insecticide, can be added to the compositions of the invention.
  • the macrocyclic lactones include, but are not limited to, avermectins such as abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin and ML- 1,694,554, and milbemycins such as milbemectin, milbemycin D, moxidectin and nemadectin. Also included are the 5-oxo and 5-oxime derivatives of said avermectins and milbemycins.
  • arylpyrazole compounds with macrocyclic lactones include but are not limited to those described in U.S. Patent Nos. 6,426,333; 6,482,425; 6,962,713 and 6,998, 131 (all incorporated herein by reference - each assigned to Merial, Ltd., Duluth, GA).
  • the macrocyclic lactone compounds are known in the art and can easily be obtained commercially or through synthesis techniques known in the art. Reference is made to the widely available technical and commercial literature.
  • avermectins ivermectin and abamectin
  • doramectin "Veterinary Parasitology", vol. 49, No.
  • milbemycins reference may be made, inter alia, to Davies H.G. et al, 1986, "Avermectins and Milbemycins", Nat. Prod. Rep., 3, 87-121, Mrozik H. et al, 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Patent No. 4,134,973 and EP 0 677 054, both incorported herein by reference.
  • Macrocyclic lactones are either natural products or are semi-synthetic derivatives thereof.
  • the structure of the avermectins and milbemycins are closely related, e.g., by sharing a complex 16-membered macrocyclic lactone ring.
  • the natural product avermectins are disclosed in U.S. Patent No. 4,310,519 and the 22,23-dihydro avermectin compounds are disclosed in U.S. Patent No. 4, 199,569. Mention is also made of U.S. Patent Nos. 4,468,390, 5,824,653, EP 0 007 812 Al, U.K. Patent Specification 1 390 336, EP 0 002 916, and New Zealand Patent No.
  • the compositions may include a class of acaricides or insecticides known as insect growth regulators (IGRs).
  • IGRs insect growth regulators
  • Compounds belonging to this group are well known to the practitioner and represent a wide range of different chemical classes. These compounds all act by interfering with the development or growth of the insect pests.
  • Insect growth regulators are described, for example, in U.S. Patent Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0 179 022 or U.K. 2 140 010 as well as U.S. Patent Nos. 6,096,329 and 6,685,954 (all incorporated herein by reference).
  • the IGR that may be included in the composition is a compound that mimics juvenile hormone.
  • juvenile hormone mimics include azadirachtin, diofenolan, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin and 4-chloro-2(2-chloro-2-methyl-propyl)-5-(6-iodo-3- pyridylmethoxy)pyridazine-3(2H)-one.
  • the compositions of the invention comprise methoprene or pyriproxyfen.
  • compositions of the invention may include an IGR compound that is a chitin synthesis inhibitor.
  • Chitin synthesis inhibitors include chlorofluazuron, cyromazine, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumoron, lufenuron, tebufenozide, teflubenzuron, triflumoron, novaluron, l-(2,6- difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea, l-(2,6-difluoro-benzoyl)-3-(2- fluoro-4-(l, l,2,2-tetrafluoroethoxy)-phenylurea and l-(2,6-difluorobenzoyl)-3-(2-fluoro-4- trifluoromethyl)phenylurea.
  • adulticide insecticides and acaricides can also be added to the composition of the invention.
  • pyrethrins which include cinerin I, cinerin II, jasmolin I, jasmolin II, pyrethrin I, pyrethrin II and mixtures thereof
  • carbamates including, but are not limited to, benomyl, carbanolate, carbaryl, carbofuran, meththiocarb, metolcarb, promacyl, propoxur, aldicarb, butocarboxim, oxamyl, thiocarboxime and thiofanox.
  • the compositions of the invention may include one or more antinematodal agents including, but not limited to, active agents in the benzimidazoles, imidazothiazoles, tetrahydropyrimidines, and organophosphate class of compounds.
  • benzimidazoles including, but not limited to, thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate and its ⁇ , ⁇ -dimethyl analogue may be included in the compositions.
  • compositions may include an imidazothiazole compounds including, but not limited to, tetramisole, levamisole and butamisole.
  • compositions of the invention may include tetrahydropyrimidine active agents including, but not limited to, pyrantel, oxantel, and morantel.
  • Suitable organophosphate active agents include, but are not limited to, coumaphos, trichlorfon, haloxon, naftalofos and dichlorvos, heptenophos, mevinphos, monocrotophos, TEPP, and tetrachlorvinphos.
  • compositions may include the antinematodal compounds phenothiazine and piperazine as the neutral compound or in various salt forms,
  • diethylcarbamazine phenols such as disophenol, arsenicals such as arsenamide,
  • ethanolamines such as bephenium, thenium closylate, and methyridine
  • cyanine dyes including pyrvinium chloride, pyrvinium pamoate and dithiazanine iodide
  • isothiocyanates including bitoscanate, suramin sodium, phthalofyne, and various natural products including, but not limited to, hygromycin B, a-santonin and kainic acid.
  • compositions of the invention may include antitrematodal agents.
  • Suitable antitrematodal agents include, but are not limited to, the miracils such as miracil D and mirasan; praziquantel, clonazepam and its 3 -methyl derivative, oltipraz, lucanthone, hycanthone, oxamniquine, amoscanate, niridazole, nitroxynil, various bisphenol compounds known in the art including hexachlorophene, bithionol, bithionol sulfoxide and menichlopholan; various salicylanilide compounds including tribromsalan, oxyclozanide, clioxanide, rafoxanide, brotianide, bromoxanide and closantel; triclabendazole, diamfenetide, clorsulon, hetolin and emetine.
  • Anticestodal compounds may also be advantageously used in the compositions of the invention including, but not limited to, arecoline in various salt forms, bunamidine, niclosamide, nitroscanate, paromomycin and paromomycin II.
  • compositions of the invention may include other active agents that are effective against arthropod parasites.
  • Suitable active agents include, but are not limited to, bromocyclen, chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos, bromophos-ethyl, carbophenothion, chlorfenvinphos, chlorpyrifos, crotoxyphos, cythioate, diazinon, dichlorenthion,, diemthoate, dioxathion, ethion, famphur, fenitrothion, fenthion, fospirate, iodofenphos, malathion, naled, phosalone, phosmet, phoxim,
  • An antiparasitic agent that can be combined with the compound of the invention to form a composition can be a biologically active peptide or protein including, but not limited to, cyclic depsipeptides, which act at the neuromuscular junction by stimulating presynaptic receptors belonging to the secretin receptor family resulting in the paralysis and death of parasites.
  • the depsipeptide is emodepside (see Willson et al, Parasitology, Jan. 2003, 126(Pt l):79-86).
  • the cyclic depsipeptide is PF 1022A (see, for example, US 5,1 16,815, which is incorporated herein by reference) or a derivative thereof.
  • the compositions may include a spinosyn active agent produced by the soil actinomycete Saccharopolyspora spinosa (see, for example Salgado V.L. and Sparks T.C., "The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance,” in Comprehensive Molecular Insect Science, vol. 6, pp. 137-173, 2005) or a semi-synthetic spinosoid active agent.
  • a spinosyn active agent produced by the soil actinomycete Saccharopolyspora spinosa (see, for example Salgado V.L. and Sparks T.C., "The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance,” in Comprehensive Molecular Insect Science, vol. 6, pp. 137-173, 2005) or a semi-synthetic spinosoid active agent.
  • the spinosyns are typically referred to as factors or components A, B, C, D, E, F, G, H, J, K, L, M, N, 0, P, Q, R, S, T, U, V, W, or Y, and any of these components, or a combination thereof, may be used in the compositions of the invention.
  • the spinosyn compound may be a 5,6,5-tricylic ring system, fused to a 12- membered macro cyclic lactone, a neutral sugar (rhamnose), and an amino sugar (forosamine).
  • spinosyn compounds including 21-butenyl spinosyn produced by Saccharopolyspora pagona, which may be used in the compositions of the invention, may be produced via fermentation by conventional techniques known in the art.
  • Other spinosyn compounds that may be used in the compositions of the invention are disclosed in U.S. Patent Nos. 5,496,931; 5,670,364; 5,591,606; 5,571,901; 5,202,242; 5,767,253; 5,840,861; 5,670,486; 5,631, 155 and 6,001,981, all incorporated by reference herein in their entirety.
  • the spinosyn compounds may include, but are not limited to, spinosyn A, spinosyn D, spinosad, spinetoram, or combinations thereof.
  • Spinosad is a combination of spinosyn A and spinosyn D
  • spinetoram is a combination of 3 '-ethoxy- 5,6-dihydro spinosyn J and 3'-ethoxy spinosyn L.
  • compositions of the invention may comprise an active agent from the neonicotinoid class of pesticides.
  • the neonicotinoids bind and inhibit insect specific nicotinic acetylcholine receptors.
  • the neonicotinoid insecticidal agent that may be included in a composition of the invention is imidacloprid.
  • Imidacloprid is a well-known neonicotinoid active agent and is the key active ingredient in the topical parasiticide products Advantage ® , Advantage ® II, K9 Advantix ® , and K9 Advantix ® II sold by Bayer Animal Health. Agents of this class are described, for example, in U.S. Patent No. 4,742,060 or in EP 0 892 060.
  • compositions of the invention may comprise nitenpyram, another active agent of the neonicotinoid class of pesticides.
  • Nitenpyram has the following chemical structure and is the active ingredient in the oral product CAPSTA TM Tablets sold by Novartis Animal Health.
  • an insecticidal agent that can be combined with the compositions of the invention is a semicarbazone, such as metaflumizone.
  • nodulisporic acid and its derivatives may be added to the compositions of the invention.
  • These compounds are used to treat or prevent infections in humans and animals and are described, for example, in U.S. Patent No. 5,399,582, 5,962,499, 6,221,894 and 6,399,786, all of which are hereby incorporated by reference in their entirety.
  • the compositions may include one or more of the known nodulisporic acid derivatives in the art, including all stereoisomers, such as those described in the patents cited above.
  • anthelmintic compounds of the amino acetonitrile class (AAD) of compounds such as monepantel (ZOLVIX), and the like may be added to the compositions of the invention.
  • AAD amino acetonitrile class
  • ZOLVIX monepantel
  • anthelmintic compounds of the amino acetonitrile class (AAD) of compounds such as monepantel (ZOLVIX), and the like may be added to the compositions of the invention.
  • AAD amino acetonitrile class
  • ZOLVIX monepantel
  • compositions of the invention may also be combined with paraherquamide compounds and derivatives of these compounds, including derquantel (see Ostlind et al,
  • the paraherquamide family of compounds is a known class of compounds that include a spirodioxepino indole core with activity against certain parasites (see Tet. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380, and J. Antibiotics 1991, 44, 492).
  • the structurally related marcfortine family of compounds such as marcfortines A- C, are also known and may be combined with the formulations of the invention (see J. Chem. Soc. - Chem. Comm. 1980, 601 and Tet. Lett.
  • compositions of the invention may advantageously include one or more compounds of the isoxazoline class of compounds. These active agents are described in WO 2007/079162, WO 2007/075459 and US
  • the anthelmintic, parasiticidal and insecticial agent may also be selected from the group of compounds described above as suitable for agrochemical use.
  • the additional active agent is included in a dose of between about 0.1 ⁇ g and about 500 mg.
  • the additional active agent may be present in a dose of about 1 mg to about 500 mg, about 1 mg to about 300 mg, or about 1 mg to about 100 mg.
  • the additional active agent may be present in a dose of about 1 mg to about 50 mg or about 1 mg to about 20 mg.
  • the additional active agent is included in a dose of about 1 ⁇ g to about 10 mg.
  • the additional active agent is included in a dose of about 5 ⁇ g/kg to about 50 mg/kg. In other embodiments, the additional active agent may be included in a dose of about 5 ⁇ g/kg to about 30 mg/kg, about 5 ⁇ g/kg to about 20 mg/kg or about 5 ⁇ g/kg to about 10 mg/kg. In still other embodiments, the additional active agent may be included in a dose of about 10 ⁇ g/kg to about 1 mg/kg or about 50 ⁇ g/kg to about 500 ⁇ g/kg of weight of the animal. In yet another embodiment of the invention, the additional active agent is included in a dose between about 0.1 mg/kg to about 10 mg/kg of weight of animal.
  • the additional active agent is included in a dose between about 0.5 mg/kg to 50 mg/kg.
  • the proportions, by weight, of the aryloazol-2-yl-cyanoethylamino compound and the additional active agent are for example between about 5/1 and about 10,000/1.
  • one of ordinary skill in the art would be able to select the appropriate ratio of aryloazol-2-yl- cyanoethylamino compound and the additional active agent for the intended host and use thereof.
  • Another aspect of the invention is the process of making the novel anthelmintic compounds of the invention.
  • the compounds of the invention may be prepared according to the processes described herein or by the application or adaptation of known methods (i.e. methods heretofore used or described in the chemical literature).
  • the compounds of the invention may be prepared by methods described in WO 2009/077527 Al, WO 2010/1 15688 Al, WO 2010/146083 Al and EP 2 468 096 Al (all incorporated herein by reference), or by adaptation of methods described in these publications.
  • Step 1 Formation of tert-butyl 4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidine- 1-carbox late.
  • Step 2 Formation of iV-[4-nitro-3-(trifluoromethyl)phenyl]piperidin-4-amine.
  • dichloromethane 10 mL
  • trifluoroacetic acid 3 ml
  • the crude material was diluted with water (50 ml), adjusted pH to 9 with sodium bicarbonate (saturated aqueous), and extracted with dichloromethane (3 x 100 ml).
  • Example 2 Preparation of iV-[4-cyano-3-(trifluoromethyl)phenyl]piperidin-4-amine. Step 1. Formation of tert-butyl 4-[[4-cyano-3-trifluoromethyl)phenyl]amino]piperidine- 1-carbox late.
  • Step 2 Formation of iV-[4-cyano-3-(trifluoromethyl)phenyl]piperidin-4-amine.
  • Example 3 Synthesis of compound #3: 4-[4-[2-oxo-2-[4-[5-(trifluoromethyl)-l,3- benzothiazol-2-yl]piperazin-l-yl]ethoxy]-l-piperidyl]-2-(trifluoromethyl)benzonitrile.
  • Step 1 Formation of 4-(4-hydroxy-l-piperidyl)-2-(trifluoromethyl)benzonitrile.
  • Step 2 Formation of tert-butyl 2-[[l-[4-cyano-3-(trifluoromethyl)phenyl]-4- pip eridyl] oxy] acetate.
  • Step 4 Formation of 4-[4-[2-oxo-2-[4-[5-(trifluoromethyl)-l,3-benzothiazol-2- yl]piperazin-l-yl]ethoxy]-l-piperidyl]-2-(trifluoromethyl)benzonitrile (Compound #3).
  • Step 1 Formation of cinnamoyl chloride. Cinnamic acid (25 g, 168.74 mmol) was treated with SOCI 2 (150 ml) for 2 hours at 70 °C in a round-bottomed flask. The volatiles were distilled out under vacuum to afford cinnamoyl chloride as a yellow oil (25.2 g, crude), which was used in the next step without further purification.
  • dichloromethane (50 ml) was added to a stirring mixture of pyridine (14.4 g, 182 mmol) and 4-dimethylaminopyridine (1.44 g, 1 1.8 mmol) in dichloromethane (100 ml) at 0 °C and stirred for 15 minutes before a solution of 4-fluoroaniline (13.2 g, 118.79 mmol) in dichloromethane (50 ml) was added over 20 min. After being stirred for 3 h at room temperature, the mixture was quenched with water (500 ml) and extracted with
  • N-(4-fluorophenyl)cinnamamide (10 g, 42 mmol) and aluminum trichloride (16.4 g, 123 mmol, 3 eq) was heated rapidly to melting and then heated at 100 °C for 3 h.
  • Step 4 Formation of 2-chloro-6-fluoroquinoline. 6-fluoro-l,2-dihydroquinolin-2-one (7.8 g, 47.8 mmol) was suspended in phosphorus oxychloride (72.2 g, 470.9 mmol) and stirred for 4 hours at 100 °C in an oil bath. The reaction mixture was concentrated under vacuum to remove the excess phosphorus oxychloride and then ice-water (200 ml) was added.
  • Example 6 Preparation of 2-(piperazin-l-yl)-6-(trifluoromethyl)quinoline. Step 1. Formation of 3,3-diethoxypropanoic acid.
  • 3,3-diethoxypropanoic acid (5 g, 30.83 mmol) was added to thionyl chloride (20 ml) with stirring at 0°C and then heated to 80°C for 1 hour (oil bath). The resulting mixture was then concentrated under vacuum to afford (2is)-3-ethoxyprop-2-enoyl chloride as dark red oil (4 g, crude).
  • 6-(trifluoromethyl)-l,2-dihydroquinolin-2-one (1.0 g, 4.7 mmol) was dissolved in POCI 3 (15 ml) and stirred for 2 h at 110°C (oil bath). The resulting mixture was dissolved in ice-water (100 ml) and adjusted pH to 8 with aqueous a 2 C0 3 solution (3N). The crude product was then extracted with dichloromethane (3 x 80 ml) and the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to afford 2- chloro-6-(trifluoromethyl)quinoline as a dark red solid (944 mg, 87 %).
  • Example 7 Preparation of l-(5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl)-piperazine. Ste 1. Formation of l-allyloxy-4-fluoro-benzene.
  • the crude material was then purified via silica gel chromatography using methanol/dichloromethane to elute.
  • the product containing fractions were then concentrated under vacuum to provide 2.2 g (45%) of the substituted piperazine as a dark red oil.
  • Example 8 Preparation of 2-chloro-l-[4-[4-(trifluoromethyl)phenyl]piperazin-l- yl]ethan-l-one. Step 1. Formation of l-[4-(trifluorometh l)phenyl] piperazine. piperazine
  • Example 9 Preparation of 7-amino-8-(trifluoromethyl)naphthalen-2-ol. Step 1. Formation of 7-methoxynaphthalen-2-ol.
  • naphthalene-2,7-diol 25 g, 156.08 mmol
  • K2CO 3 32.3 g, 232.02 mmol
  • iodomethane 22.2 g, 156.41 mmol
  • the resulting solution was stirred overnight at room temperature.
  • the solids were filtered off and the filtrate was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 1 % ⁇ 10 % ethyl acetate in petroleum ether to afford 7-methoxynaphthalen-2-ol as a light yellow solid (10 g, 37 %).
  • Step 3 Formation of l-iodo-7-methoxynaphthalen-2-amine.
  • Step 4 Formation of l-iodo-7-methoxy-2-nitronaphthalene.
  • Step 5 Formation of 7-methoxy-2-nitro-l-(trifluoromethyl)naphthalene.
  • Step 6 Formation of 7-amino-8-(trifluoromethyl)naphthalen-2-ol.
  • BBr3 4 ml, 42 mmol, 5 eq.
  • the resulting solution was stirred overnight at room temperature and then quenched by ice - water (50 ml) and extracted with dichloromethane (3 x 50 ml).
  • Example 14 Preparation of 4-[4-[2-oxo-2-[3-[[5-(trifluoromethyl)-l,3-benzothiazol-2- yl]amino]azetidin-l-yl]ethoxy]-l-piperidyl]-2-(trifluoromethyl)benzonitrile (compound # 4).
  • Step 1 Formation of tert-butyl 3-[[5-(trifluoromethyl)-l,3-benzothiazol-2- yl] amino] azetidine-l-carboxylate.
  • the 2-chlorobenzothiazole (690 mg, 2.90 mmol) was combined with 1-Boc-azetidine (500 mg, 2.90 mmol, 1 eq.) and potassium carbonate (802 mg, 5.85 mmol, 2 eq.) in 1 1 ml of DMF and stirred at RT overnight.
  • the crude reaction contents were diluted with EtOAc, washed with water, saturated aqueous LiCl, and then brine before drying over sodium sulfate.
  • Step 2 Formation of 7V-(azetidin-3-yl)-5-(trifluoromethyl)-l,3-benzothiazol-2-amine.
  • Diisopropylethylamine (1 10 ⁇ , 0.6 mmol) was added to a stirred solution of the azetidine (74 mg, 0.24 mmol), the carboxylic acid (77 mg, 0.24 mmol), and HATU (91 mg, 0.24 mmol) in 1 ml of DMF. Stirred at RT for 1 hour and the crude reaction contents were diluted with EtOAc, washed with water, saturated aqueous LiCl, and then brine before drying over sodium sulfate.
  • Example 15 Preparation of 4-[3-[2-oxo-2-[4-[5-(trifluoromethyl)-l,3-benzothiazol-2- yl]piperazin-l-yl]ethoxy]azetidin-l-yl]-2-(trifluoromethyl)benzonitrile (compound # 6).
  • Diisopropylethylamine (300 ⁇ , 1.67 mmol) was added to a stirred solution of the carboxylic acid (201 mg, 0.67 mmol), the piperazine (217 mg, 0.67 mmol), and HATU (254 mg, 0.67 mmol) in 3 ml of DMF. Stirred at RT for 1 hour and the crude reaction contents were diluted with EtOAc, washed with water, saturated aqueous LiCl, and then brine before drying over sodium sulfate.
  • METHOD A Screening method to test activity of compounds against Haemonchus contortus.
  • METHOD B Screening method to test activity of compounds against microfilaria of Dirofllaria immitis.
  • Microfilaria of Dirofllaria immitis were added to the wells of a microtitre plate containing buffer and the test compounds in DMSO. An assessment was conducted at 24 hours to determine survival of the microfilaria. Microfilaria exposed to DMSO alone served as controls. Compound 43 was found to have EC5 0 values of less than 5 ⁇ and compounds 44 & 47 returned EC5 0 values of less than 0.01 ppm.
  • Permeability of a compound across the epithelium cells along the gastrointestinal tract is an important limiting factor for the oral absorption and systemic availability of the compound.
  • An in vitro model utilizing Caco-2/TC7 cells is employed to assess the permeability characteristics of new chemical entities (NCEs).
  • NCEs new chemical entities
  • absorption depends on the intrinsic permeability across the intestinal epithelium and whether the active agent is a substrate or inhibitor of uptake or efflux transporters.
  • the permeability studies were performed under standard conditions in the apical to basolateral (A ⁇ B) direction with a pH gradient and a BSA gradient (standard apical medium (0.5% BSA at pH 6.5) / standard basal medium (5% BSA at pH 7.4)); conditions that most closely reflect the conditions in the in vivo situation.
  • Samples were deproteinized by the addition of 400 ⁇ 1 acetonitrile to 200 ⁇ 1 sample, followed by a 20-minute centrifugation at 1730 g.
  • Compound solubilisation compound solutions at final concentrations of 20 ⁇ were prepared following dilutions of stock solutions (starting from 10 mM in DMSO) in HBSS. Final concentration of DMSO was adjusted to 1%.

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9732080B2 (en) 2006-11-03 2017-08-15 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
US10081621B2 (en) 2010-03-25 2018-09-25 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US10597364B2 (en) 2015-01-20 2020-03-24 Boehringer Ingelheim Animal Health USA Inc. Anthelmintic compounds, compositions and method of using thereof
US11053234B2 (en) 2016-10-13 2021-07-06 Glaxosmithkline Intellectual Property Development Limited 1,3 di-substituted cyclobutane or azetidine derivatives as hematopoietic prostaglandin D synthase inhibitors
US11364234B2 (en) 2018-09-12 2022-06-21 The Governing Council Of The University Of Toronto Compounds and methods for treating nematode infections
US11517568B2 (en) 2018-09-12 2022-12-06 The Governing Council Of The University Of Toronto Compounds and methods for treating nematode infections

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015179414A1 (en) * 2014-05-19 2015-11-26 Merial, Inc. Anthelmintic compounds
CA3113234A1 (en) 2018-09-18 2020-03-26 Nikang Therapeutics, Inc. Tri-substituted heteroaryl derivatives as src homology-2 phosphatase inhibitors
EP3643711A1 (en) * 2018-10-24 2020-04-29 Bayer Animal Health GmbH New anthelmintic compounds

Citations (105)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2030507A1 (de) * 1970-06-20 1972-01-05 Farbenfabriken Bayer Ag, 5090 Leverkusen Oxazolyl-essigsäurederivate und Oxyzolyl-cumarine
US3748356A (en) 1970-05-15 1973-07-24 Philips Corp Substituted benzoyl ureas
US3818047A (en) 1972-08-07 1974-06-18 C Henrick Substituted pyrones
GB1390336A (en) 1972-06-08 1975-04-09 Sankyo Co Antibiotic b-41
US3950360A (en) 1972-06-08 1976-04-13 Sankyo Company Limited Antibiotic substances
US4134973A (en) 1977-04-11 1979-01-16 Merck & Co., Inc. Carbohydrate derivatives of milbemycin and processes therefor
EP0002916A2 (en) 1977-12-19 1979-07-11 Merck & Co. Inc. A milbemycin compound or a mixture thereof for use in the treatment of helminthic infections and anthelmintic compositions containing such compounds
US4166452A (en) 1976-05-03 1979-09-04 Generales Constantine D J Jr Apparatus for testing human responses to stimuli
DE2822155A1 (de) * 1978-05-20 1979-11-22 Bayer Ag Substituierte carbonsaeureamide, verfahren zu ihrer herstellung und ihre verwendung als herbizide
EP0007812A1 (en) 1978-08-02 1980-02-06 Merck & Co. Inc. Sugar derivatives of C-076 compounds, their preparation and their use as antiparasitic agents
US4199569A (en) 1977-10-03 1980-04-22 Merck & Co., Inc. Selective hydrogenation products of C-076 compounds and derivatives thereof
US4225598A (en) 1976-08-19 1980-09-30 Ciba-Geigy Corporation 2-Cyclopropylamino-4,6-diamino-s-triazine
US4256108A (en) 1977-04-07 1981-03-17 Alza Corporation Microporous-semipermeable laminated osmotic system
US4265874A (en) 1980-04-25 1981-05-05 Alza Corporation Method of delivering drug with aid of effervescent activity generated in environment of use
US4310519A (en) 1976-04-19 1982-01-12 Merck & Co., Inc. Novel substances and process for their production
US4427663A (en) 1982-03-16 1984-01-24 Merck & Co., Inc. 4"-Keto-and 4"-amino-4"-deoxy avermectin compounds and substituted amino derivatives thereof
US4468390A (en) 1981-02-23 1984-08-28 Sankyo Company, Limited Anthelmintic composition and the use thereof
GB2140010A (en) 1983-04-25 1984-11-21 Sumitomo Chemical Co Nitrogen-containing heterocyclic compounds, and their production and use
US4564631A (en) 1982-09-29 1986-01-14 Bayer Aktiengesellschaft Baits for combating vermin
EP0179022A2 (de) 1984-10-18 1986-04-23 Ciba-Geigy Ag Benzoylphenylharnstoffe
US4742060A (en) 1985-02-04 1988-05-03 Nihon Tokushu Noyaku Seizo K. K. Heterocyclic compounds
US4855317A (en) 1987-03-06 1989-08-08 Ciba-Geigy Corporation Insecticides and parasiticides
US4859657A (en) 1986-07-02 1989-08-22 Ciba-Geigy Corporation Pesticides
US4871719A (en) 1987-03-24 1989-10-03 Ciba-Geigy Corporation Composition for controlling parasites in productive livestock
US4874749A (en) 1987-07-31 1989-10-17 Merck & Co., Inc. 4"-Deoxy-4-N-methylamino avermectin Bla/Blb
US4963582A (en) 1986-03-25 1990-10-16 Sankyo Company Limited Macrolide compounds, their preparation and their use
US4978677A (en) 1986-03-06 1990-12-18 Ciba-Geigy Corporation C(29)-carbonyloxymilbemycin derivatives for controlling parasitic pets of animals and plants
WO1991009961A2 (en) 1989-12-21 1991-07-11 Beecham Group Plc Novel products
US5055596A (en) 1987-11-03 1991-10-08 Beecham Group P.L.C. Derivatives of avermectin and milbemycin
US5077308A (en) 1989-02-16 1991-12-31 Merck & Co., Inc. Avermectin ketal derivatives useful as antiparasitic
US5116815A (en) 1989-02-07 1992-05-26 Meiji Seika Kaisha Ltd. Pf 1022 substance, method of treating helminthic parasitic infection and anthelmintic composition
WO1992022555A1 (en) 1991-06-17 1992-12-23 Beecham Group Plc Paraherquamide derivatives, precursor thereof, processes for their preparation, microorganism used and their use as antiparasitic agents
US5202242A (en) 1991-11-08 1993-04-13 Dowelanco A83543 compounds and processes for production thereof
NZ237086A (en) 1991-02-12 1993-07-27 Ancare Distributors Veterinary anthelminitic drench compositions containing praziquantel and at least one other anthelmintic compound; method of treatment
US5399582A (en) 1993-11-01 1995-03-21 Merck & Co., Inc. Antiparasitic agents
EP0667054A1 (en) 1992-10-30 1995-08-16 Electric Power Research Institute, Inc Harmonic controller for an active power line conditioner
EP0677054A1 (en) 1993-01-18 1995-10-18 Pfizer Inc. New antiparasitic agents related to the milbemycins and avermectins
US5496931A (en) 1988-12-19 1996-03-05 Dowelanco Insecticide and miticide A83543 compounds and their method of production by fermentation
US5591606A (en) 1992-11-06 1997-01-07 Dowelanco Process for the production of A83543 compounds with Saccharopolyspora spinosa
WO1997003988A1 (en) 1995-07-21 1997-02-06 Pharmacia & Upjohn Company Antiparasitic marcfortines and paraherquamides
US5670486A (en) 1993-03-12 1997-09-23 Dowelanco A83543 compounds and process for production thereof
US5824653A (en) 1994-11-28 1998-10-20 Virbac S.A. Anthelmintic compositions for equidae
EP0892060A2 (en) 1997-07-18 1999-01-20 Smithkline Beecham Corporation The Chlamydia trachomatis Glutamyl-tRNAGln amidotransferase subunit ratA
US5962499A (en) 1995-03-20 1999-10-05 Merck & Co., Inc. Nodulisporic acid derivatives
US6001981A (en) 1996-06-13 1999-12-14 Dow Agrosciences Llc Synthetic modification of Spinosyn compounds
US6001384A (en) 1996-08-20 1999-12-14 Merial Method for fighting against myiasis affecting cattle and sheep populations and compositions for implementing same
US6010710A (en) 1996-03-29 2000-01-04 Merial Direct pour-on skin solution for antiparasitic use in cattle and sheep
US6083519A (en) 1996-03-29 2000-07-04 Merial N-phenylpyrazole-based anti-flea and anti-tick collar for cats and dogs
US6096329A (en) 1996-03-29 2000-08-01 Merial Insecticidal combination to control mammal fleas, in particular fleas on cats and dogs
US6174540B1 (en) 1998-09-14 2001-01-16 Merck & Co., Inc. Long acting injectable formulations containing hydrogenated caster oil
US6221894B1 (en) 1995-03-20 2001-04-24 Merck & Co., Inc. Nodulisporic acid derivatives
WO2001076370A2 (en) 2000-04-07 2001-10-18 Pharmacia & Upjohn Company Anthelmintic combinations
US6395765B1 (en) 1995-09-29 2002-05-28 Merial Antiparasitic composition for the treatment and protection of pets
US6399786B1 (en) 2000-07-14 2002-06-04 Merck & Co., Inc. Nonacyclic nodulisporic acid derivatives
US6426333B1 (en) 1996-09-19 2002-07-30 Merial Spot-on formulations for combating parasites
US6482425B1 (en) 1996-09-19 2002-11-19 Merial Parasiticidal combination
WO2004024704A1 (en) 2002-09-11 2004-03-25 Novartis Ag Organic compounds
US6787342B2 (en) 2000-02-16 2004-09-07 Merial Limited Paste formulations
WO2006014136A1 (en) * 2004-08-02 2006-02-09 Astrazeneca Ab Piperidine derivatives as histamine h3 receptor ligands
US6998131B2 (en) 1996-09-19 2006-02-14 Merial Limited Spot-on formulations for combating parasites
US7001889B2 (en) 2002-06-21 2006-02-21 Merial Limited Anthelmintic oral homogeneous veterinary pastes
US7001903B2 (en) 1998-05-26 2006-02-21 Bayer Aktiengesellschaft Synergistic insecticidal mixtures
WO2006105670A1 (en) * 2005-04-08 2006-10-12 Neuromed Pharmaceuticals Ltd. Combination therapy comprising an n-type calcium channel blocker for the alleviation of pain
WO2007016496A2 (en) * 2005-08-02 2007-02-08 Neurogen Corporation Dipiperazinyl ketones and related analogues
WO2007070606A2 (en) 2005-12-14 2007-06-21 E. I. Du Pont De Nemours And Company Isoxazolines for controlling invertebrate pests
WO2007075459A2 (en) 2005-12-16 2007-07-05 E. I. Du Pont De Nemours And Company 5-aryl isoxazolines for controlling invertebrate pests
WO2007079162A1 (en) 2005-12-30 2007-07-12 E. I. Du Pont De Nemours And Company Isoxazolines for controlling invertebrate pests
EP1932837A1 (en) * 2005-08-17 2008-06-18 Daiichi Sankyo Company, Limited Bicyclo heterocyclic compound having antifungal action
US20080146569A1 (en) * 2006-12-19 2008-06-19 Blake Tanisha D Nicotinamide Derivatives
US7420062B2 (en) 2003-07-14 2008-09-02 Bayer Cropscience, Ag Hetaryl-substituted pyrazolidindione derivatives with pesticidal characteristics
WO2008109760A2 (en) 2007-03-06 2008-09-12 Broncus Technologies, Inc. Blood vessel sensing catheter having working lumen for medical appliances
US20080234331A1 (en) 2005-11-10 2008-09-25 Bayer Cropscience Ag Synergistic Insecticidal Mixtures for the Treatment of Seed
WO2008122375A2 (en) 2007-04-10 2008-10-16 Bayer Cropscience Ag Insecticidal aryl isoxazoline derivatives
WO2008150393A1 (en) 2007-05-31 2008-12-11 E. I. Du Pont De Nemours And Company 3-cyano-4-triazolyl phenylisoxazoline invertebrate pest control agents
WO2008154528A2 (en) 2007-06-13 2008-12-18 E. I. Du Pont De Nemours And Company Isoxazoline insecticides
WO2009002809A2 (en) 2007-06-26 2008-12-31 E. I. Du Pont De Nemours And Company Naphthalene isoxazoline invertebrate pest control agents
WO2009003075A1 (en) 2007-06-27 2008-12-31 E.I. Du Pont De Nemours And Company Animal pest control method
WO2009004432A1 (en) 2007-06-29 2009-01-08 Pfizer Inc. Anthelmintic combination
WO2009024541A2 (en) 2007-08-17 2009-02-26 Intervet International B.V. Isoxazoline compositions and their use as antiparasitics
WO2009025983A2 (en) 2007-08-17 2009-02-26 E. I. Du Pont De Nemours And Company Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
WO2009045999A1 (en) 2007-10-03 2009-04-09 E. I. Du Pont De Nemours And Company Naphthalene isoxazoline compounds for control of invertebrate pests
WO2009051956A2 (en) 2007-10-16 2009-04-23 E. I. Du Pont De Nemours And Company Pyrazole-substituted isoxazoline insecticides
US20090156643A1 (en) 2006-03-10 2009-06-18 Nissan Chemical Industries, Ltd. Substituted isoxazoline compound and pesticide
WO2009077527A1 (en) 2007-12-17 2009-06-25 Intervet International B.V. Anthelmintic agents and their use
WO2009126668A2 (en) 2008-04-09 2009-10-15 E. I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
WO2009149054A1 (en) * 2008-06-03 2009-12-10 Siga Technologies, Inc. Small molecule inhibitors for the treatment or prevention of dengue virus infection
WO2010003923A1 (en) 2008-07-09 2010-01-14 Basf Se Pestcidal active mixtures comprising isoxazoline compounds i
WO2010003877A1 (en) 2008-07-09 2010-01-14 Basf Se Pesticidal mixtures comprising isoxazoline compounds ii
US7662972B2 (en) 2004-03-05 2010-02-16 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
WO2010060952A1 (en) * 2008-11-27 2010-06-03 Boehringer Ingelheim International Gmbh 6,7,8,9-tetrahydro-5h-1,4,7,10a-tetraaza-cyclohept[f]indene derivatives, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US20100137612A1 (en) 2007-06-27 2010-06-03 Nissan Chemical Industries, Ltd. Method for production of 3-hydroxypropan-1-one compound for production of 2- propen-1-one compound and method for production of isoxazline compound
US20100144797A1 (en) 2007-03-07 2010-06-10 Takeshi Mita Isoxazoline-substituted benzamide compound and pest control agent
WO2010115688A1 (en) 2009-03-20 2010-10-14 Intervet International B.V. Anthelmintic agents and their use
WO2010124121A1 (en) * 2009-04-22 2010-10-28 Jansen Pharmaceutica Nv Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitor
WO2010146083A1 (en) 2009-06-18 2010-12-23 Intervet International B.V. Anthelmintic agents and their use
US20110009438A1 (en) 2007-09-10 2011-01-13 Nissan Chemical Industries, Ltd. Substituted isoxazoline compound and pest control agent
US7964621B2 (en) 2008-10-21 2011-06-21 Merial Limited Thioamide compounds, method of making and method of using thereof
WO2011075591A1 (en) 2009-12-17 2011-06-23 Merial Limited Anti parasitic dihydroazole compounds and compositions comprising same
WO2011143365A1 (en) * 2010-05-13 2011-11-17 Amgen Inc. Nitrogen heterocyclic compounds useful as pde10 inhibitors
US8088801B2 (en) 2007-05-15 2012-01-03 Merial Limited Aryloazol-2-yl cyanoethylamino compounds, method of making and method of using thereof
US20120077797A1 (en) * 2010-09-27 2012-03-29 Connolly Peter J Oxopiperazine-azetidine amides and oxodiazepine-azetidine amides as monoacylglycerol lipase inhibitors
EP2468096A1 (en) 2010-12-21 2012-06-27 Intervet International BV Anthelmintic combinations
WO2013126856A1 (en) * 2012-02-23 2013-08-29 Vanderbilt University Substituted 5-aminothieno[2,3-c]pyridazine-6-carboxamide analogs as positive allosteric modulators of the muscarinic acetylcholine receptor m4
US20130225552A1 (en) * 2012-02-29 2013-08-29 Amgen Inc. Heterobicyclic compounds
US20140142114A1 (en) 2012-11-20 2014-05-22 Merial Limited Anthelmintic compounds and compositions and method of using thereof

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3985763A (en) 1970-06-20 1976-10-12 Bayer Aktiengesellschaft Oxazolyl-acetic acid derivatives and oxazolyl-coumarines
DE2961415D1 (en) 1978-05-20 1982-01-28 Bayer Ag Heteroaryloxy-acetamides, process for their preparation and their use as herbicides
US5795894A (en) * 1995-05-02 1998-08-18 Schering Corporation Piperazino derivatives as neurokinn antagonists
US5869488A (en) * 1996-05-01 1999-02-09 Schering Corporation Piperazino derivatives as neurokinin antagonists
GB9815880D0 (en) * 1998-07-21 1998-09-16 Pfizer Ltd Heterocycles
DE19952146A1 (de) * 1999-10-29 2001-06-07 Boehringer Ingelheim Pharma Arylalkane, Arylalkene und Aryl-azaalkane, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
YU83302A (sh) 2000-06-26 2005-09-19 Pfizer Products Inc. Jedinjenja pirolo (2,3-d) pirimidina kao imunosupresivni agensi
EP1362039B1 (en) 2001-02-16 2005-12-21 Aventis Pharmaceuticals Inc. Heterocyclic substituted carbonyl derivatives and their use as dopamine d3 receptor ligands
GB0117577D0 (en) * 2001-02-16 2001-09-12 Aventis Pharm Prod Inc Novel heterocyclic substituted carbonyl derivatives and their use as dopamine D receptor ligands
US20040006135A1 (en) * 2002-06-19 2004-01-08 Pfizer Inc. Combination treatment for depression and anxiety
TW200522944A (en) * 2003-12-23 2005-07-16 Lilly Co Eli CB1 modulator compounds
MX2007001215A (es) * 2004-08-06 2007-04-17 Otsuka Pharma Co Ltd Compuestos aromaticos.
PL1957073T3 (pl) * 2005-12-05 2014-09-30 Otsuka Pharma Co Ltd Substancja lecznicza
UA95978C2 (ru) * 2006-10-02 2011-09-26 Оцука Фармас'Ютікел Ко., Лтд. Ингибитор активации stat3/5
EP1997805A1 (en) 2007-06-01 2008-12-03 Commissariat à l'Energie Atomique Compounds with antiparasitic activity, applications thereof to the treatment of infectious diseases caused by apicomplexans
EP1997381A1 (en) * 2007-06-01 2008-12-03 Commissariat à l'Energie Atomique Use of a compound having a monogalactosyldiacylglycerol synthase inhibitory activity as herbicide or algaecide, herbicide and algaecide compositions
JP2009073743A (ja) * 2007-09-19 2009-04-09 Taiho Yakuhin Kogyo Kk 新規な縮合環式ピリミジン化合物又はその塩、及びその医薬組成物
EP2632898A4 (en) * 2010-10-29 2014-04-02 Biogen Idec Inc HETEROCYCLIC TYROSINE KINASE HEMMER
GB201115853D0 (en) * 2011-09-14 2011-10-26 Proximagen Ltd New enzyme inhibitor compounds
BR112014031375A2 (pt) * 2012-06-20 2017-06-27 Novartis Ag moduladores da série de reação complementar e usos dos mesmos
US9357782B2 (en) 2012-08-08 2016-06-07 Novartis Tiergesundheit Ag Substituted azines as pesticides
US9820488B2 (en) 2013-11-18 2017-11-21 Elanco Tiergesundheit Ag Compounds for the control of endoparasites
WO2015179414A1 (en) * 2014-05-19 2015-11-26 Merial, Inc. Anthelmintic compounds

Patent Citations (121)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3748356A (en) 1970-05-15 1973-07-24 Philips Corp Substituted benzoyl ureas
DE2030507A1 (de) * 1970-06-20 1972-01-05 Farbenfabriken Bayer Ag, 5090 Leverkusen Oxazolyl-essigsäurederivate und Oxyzolyl-cumarine
GB1390336A (en) 1972-06-08 1975-04-09 Sankyo Co Antibiotic b-41
US3950360A (en) 1972-06-08 1976-04-13 Sankyo Company Limited Antibiotic substances
US3818047A (en) 1972-08-07 1974-06-18 C Henrick Substituted pyrones
US4310519A (en) 1976-04-19 1982-01-12 Merck & Co., Inc. Novel substances and process for their production
US4166452A (en) 1976-05-03 1979-09-04 Generales Constantine D J Jr Apparatus for testing human responses to stimuli
US4225598A (en) 1976-08-19 1980-09-30 Ciba-Geigy Corporation 2-Cyclopropylamino-4,6-diamino-s-triazine
US4256108A (en) 1977-04-07 1981-03-17 Alza Corporation Microporous-semipermeable laminated osmotic system
US4134973A (en) 1977-04-11 1979-01-16 Merck & Co., Inc. Carbohydrate derivatives of milbemycin and processes therefor
US4199569A (en) 1977-10-03 1980-04-22 Merck & Co., Inc. Selective hydrogenation products of C-076 compounds and derivatives thereof
EP0002916A2 (en) 1977-12-19 1979-07-11 Merck & Co. Inc. A milbemycin compound or a mixture thereof for use in the treatment of helminthic infections and anthelmintic compositions containing such compounds
DE2822155A1 (de) * 1978-05-20 1979-11-22 Bayer Ag Substituierte carbonsaeureamide, verfahren zu ihrer herstellung und ihre verwendung als herbizide
EP0007812A1 (en) 1978-08-02 1980-02-06 Merck & Co. Inc. Sugar derivatives of C-076 compounds, their preparation and their use as antiparasitic agents
US4265874A (en) 1980-04-25 1981-05-05 Alza Corporation Method of delivering drug with aid of effervescent activity generated in environment of use
US4468390A (en) 1981-02-23 1984-08-28 Sankyo Company, Limited Anthelmintic composition and the use thereof
US4427663A (en) 1982-03-16 1984-01-24 Merck & Co., Inc. 4"-Keto-and 4"-amino-4"-deoxy avermectin compounds and substituted amino derivatives thereof
US4564631A (en) 1982-09-29 1986-01-14 Bayer Aktiengesellschaft Baits for combating vermin
GB2140010A (en) 1983-04-25 1984-11-21 Sumitomo Chemical Co Nitrogen-containing heterocyclic compounds, and their production and use
US4751225A (en) 1983-04-25 1988-06-14 Sumitomo Chemical Company, Limited Certain 2-pyridyloxy-lower alkylene-oxy-phenoxy compounds, thio-and methylene analogues having insecticidal properties
EP0179022A2 (de) 1984-10-18 1986-04-23 Ciba-Geigy Ag Benzoylphenylharnstoffe
US4798837A (en) 1984-10-18 1989-01-17 Ciba-Geigy Corporation Benzoylphenylureas
US4742060A (en) 1985-02-04 1988-05-03 Nihon Tokushu Noyaku Seizo K. K. Heterocyclic compounds
US4978677A (en) 1986-03-06 1990-12-18 Ciba-Geigy Corporation C(29)-carbonyloxymilbemycin derivatives for controlling parasitic pets of animals and plants
US4963582A (en) 1986-03-25 1990-10-16 Sankyo Company Limited Macrolide compounds, their preparation and their use
US4859657A (en) 1986-07-02 1989-08-22 Ciba-Geigy Corporation Pesticides
US4920148A (en) 1987-03-06 1990-04-24 Ciba-Geigy Corporation Insecticides and parasiticides
US4855317A (en) 1987-03-06 1989-08-08 Ciba-Geigy Corporation Insecticides and parasiticides
US4871719A (en) 1987-03-24 1989-10-03 Ciba-Geigy Corporation Composition for controlling parasites in productive livestock
US4973711A (en) 1987-03-24 1990-11-27 Ciba-Geigy Corporation Composition for controlling parasites in productive livestock
US4874749A (en) 1987-07-31 1989-10-17 Merck & Co., Inc. 4"-Deoxy-4-N-methylamino avermectin Bla/Blb
US5055596A (en) 1987-11-03 1991-10-08 Beecham Group P.L.C. Derivatives of avermectin and milbemycin
US5571901A (en) 1988-12-19 1996-11-05 Dowelanco Insecticide and miticide compositions containing A83543 compounds
US5496931A (en) 1988-12-19 1996-03-05 Dowelanco Insecticide and miticide A83543 compounds and their method of production by fermentation
US5116815A (en) 1989-02-07 1992-05-26 Meiji Seika Kaisha Ltd. Pf 1022 substance, method of treating helminthic parasitic infection and anthelmintic composition
US5077308A (en) 1989-02-16 1991-12-31 Merck & Co., Inc. Avermectin ketal derivatives useful as antiparasitic
WO1991009961A2 (en) 1989-12-21 1991-07-11 Beecham Group Plc Novel products
NZ237086A (en) 1991-02-12 1993-07-27 Ancare Distributors Veterinary anthelminitic drench compositions containing praziquantel and at least one other anthelmintic compound; method of treatment
WO1992022555A1 (en) 1991-06-17 1992-12-23 Beecham Group Plc Paraherquamide derivatives, precursor thereof, processes for their preparation, microorganism used and their use as antiparasitic agents
US5202242A (en) 1991-11-08 1993-04-13 Dowelanco A83543 compounds and processes for production thereof
EP0667054A1 (en) 1992-10-30 1995-08-16 Electric Power Research Institute, Inc Harmonic controller for an active power line conditioner
US5767253A (en) 1992-11-06 1998-06-16 Dow Agrosciences Llc A83543 Compounds; factors Q, R, S, and T
US5591606A (en) 1992-11-06 1997-01-07 Dowelanco Process for the production of A83543 compounds with Saccharopolyspora spinosa
US5631155A (en) 1992-11-06 1997-05-20 Dowelanco Saccharopolyspora spinosa strain
EP0677054A1 (en) 1993-01-18 1995-10-18 Pfizer Inc. New antiparasitic agents related to the milbemycins and avermectins
US5840861A (en) 1993-03-12 1998-11-24 Dowelanco A83543 compounds and process for production thereof
US5670486A (en) 1993-03-12 1997-09-23 Dowelanco A83543 compounds and process for production thereof
US5670364A (en) 1993-03-12 1997-09-23 Dowelanco A83543 compounds and process for production thereof
US5399582A (en) 1993-11-01 1995-03-21 Merck & Co., Inc. Antiparasitic agents
US5824653A (en) 1994-11-28 1998-10-20 Virbac S.A. Anthelmintic compositions for equidae
US5962499A (en) 1995-03-20 1999-10-05 Merck & Co., Inc. Nodulisporic acid derivatives
US6221894B1 (en) 1995-03-20 2001-04-24 Merck & Co., Inc. Nodulisporic acid derivatives
US5750695A (en) 1995-07-21 1998-05-12 Pharmacia & Upjohn Company Antiparasitic paraherquamides
US5703078A (en) 1995-07-21 1997-12-30 Pharmacia & Upjohn Company Antiparasitic marcfortines and paraherquamides
WO1997003988A1 (en) 1995-07-21 1997-02-06 Pharmacia & Upjohn Company Antiparasitic marcfortines and paraherquamides
US6395765B1 (en) 1995-09-29 2002-05-28 Merial Antiparasitic composition for the treatment and protection of pets
US6096329A (en) 1996-03-29 2000-08-01 Merial Insecticidal combination to control mammal fleas, in particular fleas on cats and dogs
US6685954B2 (en) 1996-03-29 2004-02-03 Merial Insecticidal combination to control mammal fleas, in particular fleas on cats and dogs
US6083519A (en) 1996-03-29 2000-07-04 Merial N-phenylpyrazole-based anti-flea and anti-tick collar for cats and dogs
US6010710A (en) 1996-03-29 2000-01-04 Merial Direct pour-on skin solution for antiparasitic use in cattle and sheep
US6001981A (en) 1996-06-13 1999-12-14 Dow Agrosciences Llc Synthetic modification of Spinosyn compounds
US6001384A (en) 1996-08-20 1999-12-14 Merial Method for fighting against myiasis affecting cattle and sheep populations and compositions for implementing same
US6426333B1 (en) 1996-09-19 2002-07-30 Merial Spot-on formulations for combating parasites
US6482425B1 (en) 1996-09-19 2002-11-19 Merial Parasiticidal combination
US6962713B2 (en) 1996-09-19 2005-11-08 Merial Spot-on formulations for combating parasites
US6998131B2 (en) 1996-09-19 2006-02-14 Merial Limited Spot-on formulations for combating parasites
EP0892060A2 (en) 1997-07-18 1999-01-20 Smithkline Beecham Corporation The Chlamydia trachomatis Glutamyl-tRNAGln amidotransferase subunit ratA
US7001903B2 (en) 1998-05-26 2006-02-21 Bayer Aktiengesellschaft Synergistic insecticidal mixtures
US6174540B1 (en) 1998-09-14 2001-01-16 Merck & Co., Inc. Long acting injectable formulations containing hydrogenated caster oil
US6787342B2 (en) 2000-02-16 2004-09-07 Merial Limited Paste formulations
WO2001076370A2 (en) 2000-04-07 2001-10-18 Pharmacia & Upjohn Company Anthelmintic combinations
US6399786B1 (en) 2000-07-14 2002-06-04 Merck & Co., Inc. Nonacyclic nodulisporic acid derivatives
US7001889B2 (en) 2002-06-21 2006-02-21 Merial Limited Anthelmintic oral homogeneous veterinary pastes
US7084280B2 (en) 2002-09-11 2006-08-01 Pierre Ducray Benzotriazol-1-yl-aminoacetonitrile compounds and their use in the control of parasite disease
WO2004024704A1 (en) 2002-09-11 2004-03-25 Novartis Ag Organic compounds
US7420062B2 (en) 2003-07-14 2008-09-02 Bayer Cropscience, Ag Hetaryl-substituted pyrazolidindione derivatives with pesticidal characteristics
US7662972B2 (en) 2004-03-05 2010-02-16 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
WO2006014136A1 (en) * 2004-08-02 2006-02-09 Astrazeneca Ab Piperidine derivatives as histamine h3 receptor ligands
WO2006105670A1 (en) * 2005-04-08 2006-10-12 Neuromed Pharmaceuticals Ltd. Combination therapy comprising an n-type calcium channel blocker for the alleviation of pain
WO2007016496A2 (en) * 2005-08-02 2007-02-08 Neurogen Corporation Dipiperazinyl ketones and related analogues
EP1932837A1 (en) * 2005-08-17 2008-06-18 Daiichi Sankyo Company, Limited Bicyclo heterocyclic compound having antifungal action
US20080234331A1 (en) 2005-11-10 2008-09-25 Bayer Cropscience Ag Synergistic Insecticidal Mixtures for the Treatment of Seed
US20090143410A1 (en) 2005-12-14 2009-06-04 Kanu Maganbhai Patel Isoxazolines for Controlling Invertebrate Pests
WO2007070606A2 (en) 2005-12-14 2007-06-21 E. I. Du Pont De Nemours And Company Isoxazolines for controlling invertebrate pests
WO2007075459A2 (en) 2005-12-16 2007-07-05 E. I. Du Pont De Nemours And Company 5-aryl isoxazolines for controlling invertebrate pests
US20090133319A1 (en) 2005-12-16 2009-05-28 E. I. Du Pont De Nemours And Company 5-Aryl Isoxazolines for Controlling Invertebrate Pests
WO2007079162A1 (en) 2005-12-30 2007-07-12 E. I. Du Pont De Nemours And Company Isoxazolines for controlling invertebrate pests
US20090156643A1 (en) 2006-03-10 2009-06-18 Nissan Chemical Industries, Ltd. Substituted isoxazoline compound and pesticide
US20080146569A1 (en) * 2006-12-19 2008-06-19 Blake Tanisha D Nicotinamide Derivatives
WO2008109760A2 (en) 2007-03-06 2008-09-12 Broncus Technologies, Inc. Blood vessel sensing catheter having working lumen for medical appliances
US20100144797A1 (en) 2007-03-07 2010-06-10 Takeshi Mita Isoxazoline-substituted benzamide compound and pest control agent
WO2008122375A2 (en) 2007-04-10 2008-10-16 Bayer Cropscience Ag Insecticidal aryl isoxazoline derivatives
US8088801B2 (en) 2007-05-15 2012-01-03 Merial Limited Aryloazol-2-yl cyanoethylamino compounds, method of making and method of using thereof
WO2008150393A1 (en) 2007-05-31 2008-12-11 E. I. Du Pont De Nemours And Company 3-cyano-4-triazolyl phenylisoxazoline invertebrate pest control agents
WO2008154528A2 (en) 2007-06-13 2008-12-18 E. I. Du Pont De Nemours And Company Isoxazoline insecticides
WO2009002809A2 (en) 2007-06-26 2008-12-31 E. I. Du Pont De Nemours And Company Naphthalene isoxazoline invertebrate pest control agents
WO2009003075A1 (en) 2007-06-27 2008-12-31 E.I. Du Pont De Nemours And Company Animal pest control method
US20100137612A1 (en) 2007-06-27 2010-06-03 Nissan Chemical Industries, Ltd. Method for production of 3-hydroxypropan-1-one compound for production of 2- propen-1-one compound and method for production of isoxazline compound
WO2009004432A1 (en) 2007-06-29 2009-01-08 Pfizer Inc. Anthelmintic combination
WO2009025983A2 (en) 2007-08-17 2009-02-26 E. I. Du Pont De Nemours And Company Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
WO2009024541A2 (en) 2007-08-17 2009-02-26 Intervet International B.V. Isoxazoline compositions and their use as antiparasitics
US20110009438A1 (en) 2007-09-10 2011-01-13 Nissan Chemical Industries, Ltd. Substituted isoxazoline compound and pest control agent
WO2009045999A1 (en) 2007-10-03 2009-04-09 E. I. Du Pont De Nemours And Company Naphthalene isoxazoline compounds for control of invertebrate pests
WO2009051956A2 (en) 2007-10-16 2009-04-23 E. I. Du Pont De Nemours And Company Pyrazole-substituted isoxazoline insecticides
WO2009077527A1 (en) 2007-12-17 2009-06-25 Intervet International B.V. Anthelmintic agents and their use
WO2009126668A2 (en) 2008-04-09 2009-10-15 E. I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
WO2009149054A1 (en) * 2008-06-03 2009-12-10 Siga Technologies, Inc. Small molecule inhibitors for the treatment or prevention of dengue virus infection
WO2010003923A1 (en) 2008-07-09 2010-01-14 Basf Se Pestcidal active mixtures comprising isoxazoline compounds i
WO2010003877A1 (en) 2008-07-09 2010-01-14 Basf Se Pesticidal mixtures comprising isoxazoline compounds ii
US7964621B2 (en) 2008-10-21 2011-06-21 Merial Limited Thioamide compounds, method of making and method of using thereof
WO2010060952A1 (en) * 2008-11-27 2010-06-03 Boehringer Ingelheim International Gmbh 6,7,8,9-tetrahydro-5h-1,4,7,10a-tetraaza-cyclohept[f]indene derivatives, pharmaceutical compositions containing these compounds, their use and processes for preparing them
WO2010115688A1 (en) 2009-03-20 2010-10-14 Intervet International B.V. Anthelmintic agents and their use
WO2010124121A1 (en) * 2009-04-22 2010-10-28 Jansen Pharmaceutica Nv Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitor
WO2010146083A1 (en) 2009-06-18 2010-12-23 Intervet International B.V. Anthelmintic agents and their use
WO2011075591A1 (en) 2009-12-17 2011-06-23 Merial Limited Anti parasitic dihydroazole compounds and compositions comprising same
WO2011143365A1 (en) * 2010-05-13 2011-11-17 Amgen Inc. Nitrogen heterocyclic compounds useful as pde10 inhibitors
US20120077797A1 (en) * 2010-09-27 2012-03-29 Connolly Peter J Oxopiperazine-azetidine amides and oxodiazepine-azetidine amides as monoacylglycerol lipase inhibitors
EP2468096A1 (en) 2010-12-21 2012-06-27 Intervet International BV Anthelmintic combinations
WO2013126856A1 (en) * 2012-02-23 2013-08-29 Vanderbilt University Substituted 5-aminothieno[2,3-c]pyridazine-6-carboxamide analogs as positive allosteric modulators of the muscarinic acetylcholine receptor m4
US20130225552A1 (en) * 2012-02-29 2013-08-29 Amgen Inc. Heterobicyclic compounds
US20140142114A1 (en) 2012-11-20 2014-05-22 Merial Limited Anthelmintic compounds and compositions and method of using thereof

Non-Patent Citations (40)

* Cited by examiner, † Cited by third party
Title
"International Nonproprietary Names for Pharmaceutical Substances (INN", WHO DRUG INFORMATION, vol. 17, no. 4, 2003, pages 263 - 286
"Perry's Chemical Engineer's Handbook, 5th Ed.", 1973, MCGRAW-HILL, pages: 8 - 57
"Spray-Drying Handbook 3rd ed.", 1979, G. GOODWIN LTD.
.: "Detergents and Emulsifiers Annual", MC PUBL. CORP.
ALBERS-SCHONBERG ET AL.: "Avermectins Structure Determination", J. AM. CHEM. SOC., vol. 103, 1981, pages 4216 - 4221
BYRN ET AL.: "Solid-State Chemistry of Drugs 2nd Edition,", 1999, SSCI INC.
C. MARSDEN: "Solvents Guide 2nd Ed.,", 1963, INTERSCIENCE
CHHAJED SANTOSH S ET AL: "Synthesis and molecular modeling studies of 3-chloro-4-substituted-1-(8-hydroxy-quinolin-5-yl)-azetidin-2-ones as novel anti-filarial agents", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 20, no. 12, 20 October 2000 (2000-10-20), pages 3640 - 3644, XP029120970, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2010.04.106 *
CHOI YEON-HEE ET AL: "Facile synthesis and biological evaluation of 3,3-diphenylpropanoyl piperazines as T-type calcium channel blockers", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 21, no. 1, 2011, pages 215 - 219, XP029121251, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2010.11.033 *
DAVIES H.G. ET AL.: "Avermectins and Milbemycins", NAT. PROD. REP., vol. 3, 1986, pages 87 - 121
DONALD C. PLUMB: "Plumb' Veterinary Drug Handbook, 5th Ed.", 2005, BLACKWELL PUBLISHING
GLUSKER ET AL.: "Crystal Structure Analysis - A Primer, 2nd Edition,", 1985, OXFORD UNIVERSITY PRESS
GREENE ET AL.: "Protective Groups in Organic Synthesis, Third Edition,", 1999, JOHN WILEY AND SONS
H.V. OLPHEN: "Introduction to Clay Colloid Chemistry, 2nd Ed.,", J. WILEY & SONS
HAUGWITZ R D ET AL: "Antiparasitic agents. 5. Synthesis and anthelmintic activities of novel 2-heteroaromatic-substituted isothiocyanatobenzoxazoles and benzothiazoles", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 25, no. 8, 1 August 1982 (1982-08-01), pages 969 - 974, XP002374845, ISSN: 0022-2623, DOI: 10.1021/JM00350A017 *
J ANTIBIOTICS, vol. 44, 1991, pages 492
J. ANTIBIOTICS, vol. 43, 1990, pages 1380
J. CHEM. SOC. - CHEM. COMM., 1980, pages 601
J.E. BROWNING: "Agglomeration", CHEMICAL AND ENGINEERING, 1967, pages 147
K. MARTENS: "Spray Drying Handbook, 3rd Ed.", 1979, G. GOODWIN LTD.
KAMINSKY ET AL., NATURE, vol. 452, 13 March 2008 (2008-03-13), pages 176 - 181
M.H. FISCHER; H. MROZIK; WILLIAM C. CAMPBELL: "Ivermectin and Abamectin", 1989, SPRINGER VERLAG.
MELANCON BRUCE J ET AL: "Development of a more highly selective M1antagonist from the continued optimization of the MLPCN Probe ML012", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 22, no. 2, 6 December 2011 (2011-12-06), pages 1044 - 1048, XP029121658, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2011.11.110 *
MERCK: "The Merck Veterinary Manual, 9th Edition", January 2005
MROZIK H. ET AL.: "Synthesis of Milbemycins from Avermectins", TETRAHEDRON LETT., vol. 24, 1983, pages 5333 - 5336
OSTLIND ET AL., MEDICAL AND VETERINARY ENTOMOLOGY, vol. 11, 1997, pages 407 - 408
OSTLIND ET AL., RESEARCH IN VETERINARY SCIENCE, vol. 48, 1990, pages 260 - 61
S. BUDAVARI,: "The Merck Index, 12 ed.,", 1996, MERCK & CO., INC.
SAGER ET AL., VETERINARY PARASITOLOGY, vol. 159, 2009, pages 49 - 54
SALGADO V.L.; SPARKS T.C.: "The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance", COMPREHENSIVE MOLECULAR INSECT SCIENCE, vol. 6, 2005, pages 137 - 73
SCH6NFELDT: "Grenzflachenaktive Athylenoxidaddukte", 1976, WISS. VERLAGSGESELL.
SISLEY; WOOD: "Encyclopedia of Surface Active Agents", 1964, CHEM. PUBL. CO. INC.
TET. LETT., vol. 22, 1981, pages 135
TET. LETT., vol. 22, 1981, pages 1977
VETERINARY PARASITOLOGY, vol. 49, no. 1, July 1993 (1993-07-01), pages 5 - 15
WADE VAN VALKENBURG: "Pesticide Formulations", 1973, MARCEL DEKKER
WATKINS: "Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed.,", DARLAND BOOKS
WILLSON ET AL., PARASITOLOGY, vol. 126, January 2003 (2003-01-01), pages 79 - 86
WINNACKER-KUCHLER: "Chemische Technologie, 4th Edition", vol. 7, 1986, C. HAUSER VERLAG
XUEQING WANG ET AL: "Synthesis and Evaluation of Benzothiazole-Based Analogues as Novel, Potent, and Selective Fatty Acid Amide Hydrolase Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, no. 1, 8 January 2009 (2009-01-08), pages 170 - 180, XP055028951, ISSN: 0022-2623, DOI: 10.1021/jm801042a *

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